3-spiro-7-hydroxamic acid tetralins as HDAC inhibitors

ABSTRACT

The present invention is directed to inhibitors of histone deacetylases (HDACs) such as HDAC6, and their use in the treatment of diseases such as cell proliferative diseases (e.g., cancer), neurological (e.g., neurodegenerative disease or neurodevelopmental disease), inflammatory or autoimmune disease, infection, metabolic disease, hematologic disease, or cardiovascular disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. 62/149,360, filed Apr. 17, 2015, the contents of whichare hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisinvention is concerned with compounds and compositions inhibiting HDACs,methods of treating diseases associated with HDACs, and methods ofsynthesizing these compounds.

BACKGROUND OF THE INVENTION

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 6 (HDAC6) is azinc-dependent histone deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-5 and 7-11. (De Ruijteret al, Biochem. J. 2003. 370; 737-749).

HDAC6 is known to deacetylate and associate with α-tubulin, cortactin,heat shock protein 90, β-catenin, glucose-regulated protein 78 kDa,myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homologsubfamily A member 1 (reviewed in Li et al, FEBS J. 2013, 280: 775-93;Zhang et al, Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6inhibition could have a potential benefit include cancer (reviewed inAldana-Masangkay et al, J. Biomed. Biotechnol. 2011, 875824),specifically: multiple myeloma (Hideshima et al, Proc. Natl. Acad. Sci.USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al, Biochem.Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro etal, Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al,Cancer Res. 2008, 68(18):7561-7569; Park et al, Oncol. Rep. 2011, 25:1677-81; Rey et al, Eur. J. Cell Biol. 2011, 90: 128-35); prostatecancer (Seidel et al, Biochem. Pharmacol. 2015 (15)00714-5); pancreaticcancer (Nawrocki et al, Cancer Res. 2006, 66(7):3773-3781); renal cancer(Cha et al, Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellularcancer (Ding et al, FEBS Lett. 2013, 587:880-6; Kanno et al, Oncol. Rep.2012, 28: 867-73); lymphomas (Ding et al, Cancer Cell Int. 2014, 14:139;Amengual et al, Clin Cancer Res. 2015, 21(20):4663-75); and leukemiassuch as acute myeloid leukemia (AML) (Fiskus et al, Blood 2008,112(7):2896-2905) and acute lymphoblastic leukemia (ALL)(Rodriguez-Gonzalez et al, Blood 2008, 112(11): Abstract 1923)).

Inhibition of HDAC6 may also have a role in cardiovascular disease,including pressure overload, chronic ischemia, andinfarction-reperfusion injury (Tannous et al, Circulation 2008, 117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Alzheimer's, Parkinson's andHuntington's disease (reviewed in Simoes-Pires et al, Mol. Neurodegener.2013, 8: 7) or central nervous system trauma caused by tissue injury,oxidative-stress induced neuronal or axomal degeneration (Rivieccio etal, Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); andinflammation and autoimmune diseases through enhanced T cell-mediatedimmune tolerance at least in part through effects on regulatory T cells,including rheumatoid arthritis, psoriasis, spondylitis arthritis,psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versushost disease (reviewed in Wang et al, Nat. Rev. Drug Disc. 20098(12):969-981; Vishwakarma et al, Int. Immunopharmacol. 2013, 16:72-8;Kalin et al, J. Med. Chem. 2012, 55:639-51); and fibrotic disease,including kidney fibrosis (Choi et al, Vascul. Pharmacol. 201572:130-140).

Four HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment ofmultiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatmentof peripheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus there isa need for HDAC inhibitors with an improved safety-efficacy profile.

SUMMARY OF THE INVENTION

One aspect of the invention relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, or isomers or thereof, wherein:

X¹, X², X³, X⁶, and X⁷ are each independently —CR¹R²—, —NR³—, —O—,—C(O)—, —SO₂—, —S(O)—, or —S—;

X⁴ and X⁵ are each independently —CR¹R²—, —C(O)—, —SO₂—, —S(O)—, or —S—;

Y¹, Y³ and Y⁴ are each independently N or CR¹;

L is a bond, —(CR¹R²)_(n)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(n)O—, or —C(O)(CR¹R²)_(n)—;

R is independently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₅-C₁₂spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatomsselected from the group consisting of N, S, P, or O, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl is optionally substituted withone or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —SR³, —OR³, —NHR³,—NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, or heteroaryl;

R¹ and R² are independently, at each occurrence, —H, —R³, —R⁴,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, or (CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more —OH, halogen,—NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴, —S(O)₂N(R³)₂—, —S(O)₂R⁵,—C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵,heterocycle, aryl, or heteroaryl;

or R¹ and R² can combine with the carbon atom to which they are bothattached to form a cycloalkyl, heterocycle, spirocycle,spiroheterocycle, or spirocycloalkenyl;

or R¹ and R², when on adjacent or non-adjacent atoms, can combine toform a heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, orcycloalkenyl;

R³ and R⁴ are independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromN, S, P, and O, —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, or—(CHR⁵)_(n)N(C₁-C₆alkyl)₂, wherein each alkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with one or more substituents selected from —OH, halogen,—NO₂, oxo, —CN, —R⁵, —O(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkly)₂,—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂NHC₁-C₆alkyl, —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, —S(O)R⁵,—S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)R⁵, heterocycle, aryl, orheteroaryl;

R⁵ is independently, at each occurrence, —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl)or —(CH₂)_(n)N(C₁-C₆alkyl)₂;

n is an integer from 0 to 6; and

m is 0, 1, 2 or 3.

In another aspect, the invention relates to compounds of Formula II:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers or isomers thereof, wherein:

X¹ is independently —CR¹R²—, —NR³—, —O—, —SO₂—, —S(O)—, or —S—;

X², X³, X⁴, and X⁷ are each independently —CR¹R²—, —NR³—, —O—, —C(O)—,—SO₂—, —S(O)—, or —S—;

X⁵ and X⁶ are each independently —CR¹R²—, —C(O)—, —SO₂—, —S(O)—, or —S—;

Y¹, Y³ and Y⁴ are each independently N or CR¹;

L is a bond, —(CR¹R²)_(n)—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—,—S(O)NR³—, —C(O)(CR¹R²)_(n)O—, or —C(O)(CR¹R²)_(n)—;

R is independently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₅-C₁₂spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatomsselected from the group consisting of N, S, P, or O, wherein each-alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R²,—SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, orheteroaryl;

R¹ and R² are independently, and at each occurrence, —H, —R³, —R⁴,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, or O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, or (CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more substituentsselected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴,—S(O)₂N(R³)₂—, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, or heteroaryl;

or R¹ and R² can combine with the carbon atom to which they are bothattached to form a cycloalkyl, heterocycle, spirocycle,spiroheterocycle, or spirocycloalkenyl;

or R¹ and R², when on adjacent or non-adjacent atoms, can combine toform a heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, orcycloalkenyl;

R³ and R⁴ are independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromN, S, P and O, —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, or—(CHR⁵)_(n)N(C₁-C₆alkyl)₂, wherein each alkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with one or more substituents selected from —OH, halogen,—NO₂, oxo, —CN, —R⁵, —O(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkly)₂,—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂NHC₁-C₆alkyl, —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, —S(O)R⁵,—S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)R⁵, heterocycle, aryl, orheteroaryl;

each R⁵ is independently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from N, S, O and P, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl)or —(CH₂)_(n)N(C₁-C₆alkyl)₂; and

n is an integer from 0 to 6.

Another aspect of the invention relates to a method of treating adisease or disorder associated with HDAC6 modulation in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of Formula I or Formula II.

Another aspect of the invention is directed to a method of inhibitingHDAC6. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula I or Formula II.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I or Formula II and apharmaceutically acceptable carrier. The pharmaceutically acceptablecarrier can further include an excipient, diluent, or surfactant. Thepharmaceutical composition can be effective for treating a disease ordisorder associated with HDAC6 modulation in a subject in need thereof.The pharmaceutical compositions can comprise the compounds of thepresent invention for use in treating diseases described herein.

The compositions can contain at least one compound of the invention anda pharmaceutically acceptable carrier. The invention also provides theuse of the compounds described herein in the manufacture of a medicamentfor the treatment of a disease associated with HDACs.

The present invention also provides methods for the treatment of humandiseases or disorders including, without limitation, oncological,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present invention also provides compounds that are useful ininhibiting of zinc-dependent HDAC enzymes, and in particular HDAC6.These compounds can also be useful in the treatment of diseasesincluding cancer,

The present invention further provides compounds that can inhibit HDAC6.In some embodiments, the efficacy-safety profile of the compounds of thecurrent invention can be improved relative to other known HDAC (e.g.HDAC6) inhibitors. Additionally, the present technology also has theadvantage of being able to be used for a number of different types ofdiseases, including cancer and non-cancer indications. Additionalfeatures and advantages of the present technology will be apparent toone of skill in the art upon reading the Detailed Description of theInvention, below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray crystal structure of methyl(R)-1′-[(4-methanesulfonylphenyl)methyl]-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate.

DETAILED DESCRIPTION OF THE INVENTION

HDAC6 is a zinc-dependent histone deacetylase that has two catalyticdomains. HDAC6 can interact with and deacetylate non-histone proteins,including HSP90 and α-tubulin. Acetylation of HSP90 is associated withloss of function of HSP90. HDAC6 is also implicated in the degradationof misfolded proteins as part of the aggresome. Accordingly, inhibitionof HDAC6 can have downstream effects that can play a role in thedevelopment of certain diseases such as cancer. The present inventionprovides inhibitors of HDAC6 and methods for using the same to treatdisease.

In a first aspect of the invention, compounds of the Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein m, R, L, X¹, X², X³, X⁴, X⁵, X⁶,X⁷, Y¹, Y³, and Y⁴ are described as above.

In a second aspect of the invention, compounds of the Formula II aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein R, L, X¹, X², X³, X⁴, X⁵, X⁶,X⁷, Y¹, Y³, and Y⁴ are described as above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆alkyl,—C₁-C₆alkyl, —OC₂-C₆alkenyl, —OC₂-C₆alkynyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl, —C(O)C₁-C₆alkyl,—OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,—S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and —S(O)N(C₁-C₆alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, S, P, and O, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, S, P, and O. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl,benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkylgroup include, but are not limited to, methyl, ethyl, propyl, butyl,pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl andneopentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Certain alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Certain alkynyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 4-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₄-C₈ cycloalkenyl is acycloalkenyl group containing between 4 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, phosphorous nitrogen, or sulfur andwherein there is not delocalized π electrons (aromaticity) shared amongthe ring carbon or heteroatoms. Heterocyclyl rings include, but are notlimited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl,thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heteroycyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means a fluoro, chloro,bromo, or iodo group.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

“Spirocycle” or “spirocyclic” means carbogenic bicyclic ring systemswith both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spirohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A C₅-C₁₂spirocycle is a spirocycle containing between 5 and 12 carbon atoms. Oneor more of the carbon atoms can be substituted with a heteroatom.

The term “spirocyclic heterocycle” or “spiroheterocycle” is understoodto mean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl). A spirocyclic heterocycle can contain between 5 and 12atoms, at least one of which is a heteroatom selected from N, O, S andP.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the invention.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(i.e., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I or Formula II mayhave one or more asymmetric carbon atom and may occur as racemates,racemic mixtures and as individual enantiomers or diastereomers.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In one embodiments of the compounds of Formula I or Formula II, X⁴ is—C(O)—.

In one or more embodiments of the compounds of Formula I, m is 0 or 1.

In one or more embodiments of the compounds of Formula I and Formula II,Y¹, Y³ and Y⁴ are each CR¹.

In one embodiment of the compound of Formula I, the compound is of theFormula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, or I-m:

In one embodiment of the compound of Formula II, the compound is of theFormula II-a, II-b, II-c, II-d or II-e:

In an illustrative embodiment, a compound of Formula I can be selectedfrom:

-   1′-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-1);-   N-hydroxy-1′-(4-methoxyphenethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-2);-   N-hydroxy-1′-(4-methoxybenzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-3);-   N-hydroxy-1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-4);-   1′-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-5);-   1′-(3,4-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-6);-   1′-(cyclohexylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-7);-   N-hydroxy-1′-(4-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-8);-   1′-(3-(dimethylamino)propyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-9);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-10);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-11);-   (R)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-12);-   (S)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-13);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-14);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-15);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-16);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-17);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-18);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-19);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-20);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-21);-   (R)-N-hydroxy-1′-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-22);-   (S)-N-hydroxy-1′-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-23);-   (R)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-24);-   (S)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-25);-   (R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-26);-   (R)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-27);-   (S)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-28);-   (S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-29);-   (R)-1′-((2-chlorothiazol-5-yl)methyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-30);-   (R)-N-hydroxy-1′-((2-hydroxythiazol-5-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-31);-   (R)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-32);-   (R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-33);-   (R)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-34);-   (R)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-35);-   (R)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-36);-   (R)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-37);-   (R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-38);-   (R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-39);-   (R)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-40);-   (R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-41);-   (R)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-42);-   (R)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-43);-   (R)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-44);-   (R)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-45);-   (R)-N-hydroxy-1′-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-46);-   (R)-N-hydroxy-1′-(2-methylallyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-47);-   (R)-1′-(2,5-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-48);-   (R)-1′-(2,6-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-49);-   (R)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-50);-   (R)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-51);-   (R)-N-hydroxy-2′-oxo-1′-(pyridin-2-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-52);-   (R)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-53);-   (R)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-54);-   (R)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-55);-   (R)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-56);-   (R)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-57);-   (R)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-58);-   (R)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-59);-   (S)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-60);-   (S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-61);-   (S)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-62);-   (S)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-63);-   (S)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-64);-   (S)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-65);-   (S)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-66);-   (S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-67);-   (S)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-68);-   (S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-69);-   (S)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-70);-   (S)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-71);-   (S)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-72);-   (S)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-73);-   (S)-1′-(2,5-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-74);-   (S)-1′-(2,6-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-75);-   (S)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-76);-   (S)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-77);-   (S)-N-hydroxy-2′-oxo-1′-(pyridin-2-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-78);-   (S)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-79);-   (S)-N-hydroxy-2′-oxo-1′-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-80);-   (S)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-81);-   (S)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-82);-   (S)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-83);-   (S)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-84);-   (S)-1′-(4-(tert-butyl)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-85);-   (S)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-86);-   (S)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-87);-   (R)-N-hydroxy-1′-(4-(methylsulfonyl)benzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-88);-   (R)-N-hydroxy-1′-(naphthalen-1-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-89);-   (R)-1′-(3-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-90);-   (R)-1′-(benzo[d][1,3]dioxol-5-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-91);-   (R)-N-hydroxy-1′-(3-(methylthio)phenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-92);-   (R)-1′-(4-(dimethylamino)phenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-93);-   (R)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-94);-   (R)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-95);-   (R)-1′-(2,3-dihydrobenzofuran-7-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-96);-   (R)-1′-(6-(tert-butylamino)pyrimidin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-97);-   (R)-1′-(1,3-dimethyl-1H-pyrazol-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-98);-   (R)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-99);-   (S)-1′-(2,4-dimethylphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-100);-   (S)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-101);-   (S)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-102);-   (S)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-103);-   (R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-104);-   (S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-105);-   (R)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-106);-   (S)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-107);-   (R)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-108);-   (R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-109);-   (R)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-110);-   (R)-N-hydroxy-1′-(2-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-111);-   (R)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-112);-   (R)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-113);-   (R)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-114);-   (S)-N-hydroxy-1′-(2-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-115);-   (S)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-116);-   (S)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-117);-   (S)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-118);-   (R)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-119);-   (R)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-120);-   (R)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-121);-   (S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-122);-   (R)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-123);-   (R)-N-hydroxy-1′-(4-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-124);-   (R)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-125);-   (S)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-126);-   (S)-1′-(2-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-127);-   (R)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-128);-   (S)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-129);-   (S)-1′-(5-chloropyridin-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-130);-   (R)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-131);-   (S)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-132);-   (R)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-133);-   (S)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-134);-   (R)-N-hydroxy-1′-(5-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-135);-   (R)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-136);-   (S)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-137);-   (R)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-138);-   (S)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-139);-   (R)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-140);-   (S)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-141);-   (S)-N-hydroxy-1′-(4-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-142);-   (R)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-143);-   (S)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-144);-   (R)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-145);-   (S)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-146);-   (S)-1′-(2-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-147);-   (S)-1′-(3-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-148);-   (R)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-149);-   (S)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-150);-   (R)-1′-(6-(dimethylamino)pyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-151);-   (S)-1′-(6-(dimethylamino)pyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-152);-   (S)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-153);-   (S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-154);-   (S)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-155);-   (S)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-156);-   (S)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-157);-   (S)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-158);-   (R)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-159);-   (S)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-160);-   (R)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-161);-   (S)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-162);-   (R)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-163);-   (S)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-164);-   (R)-N-hydroxy-2′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-165);-   (S)-N-hydroxy-2′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-166);-   (R)-1′-(2,    5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-167);-   (R)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-168);-   (S)-1′-(2,5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-169);-   (S)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-170);-   (R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-171);-   (S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-172);-   (S)-1′-(4-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-173);-   (S)-1′-(2-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-174);-   (R)-1′-(2-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-175);-   1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-176);-   N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-177);-   N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-178);-   (R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-179);-   (S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-180);-   (R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-181);-   (S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-182);-   (S)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-183);-   (S)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-184);-   (R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-185);-   (S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-186);-   (R)-N-hydroxy-1′-(3-methoxypropyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-187);-   (S)-N-hydroxy-1′-(3-methoxypropyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-188);-   (R)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-189);-   (S)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-190);-   (R)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-191);-   (S)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-192);-   (R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-193);-   (R)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-194);-   (S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-195);-   (R)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-196);-   (R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-197);-   (S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-198);-   (R)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-199);-   (S)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-200);-   (R)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-201);-   (S)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-202);-   (R)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-203);-   (S)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-204);-   (R)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-205);-   (R)-1′-ethyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-206);-   (R)-N-hydroxy-1′-isobutyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-207);-   (R)-N-hydroxy-1′-isopropyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-208);-   (R)-1′-cyclopropyl-N-hydroxy-5′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-209);-   (S)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-210);-   (S)-1′-ethyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-211);-   (S)-N-hydroxy-1′-isobutyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-212);-   (S)-N-hydroxy-1′-isopropyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-213);-   (S)-1′-cyclopropyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-214);-   (R)-N-hydroxy-1′-(oxetan-3-ylmethyl)-5′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-215);-   (R)-1′-benzyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-216);-   (S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-217);-   (S)-1′-benzyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-218);-   (R)-N-hydroxy-1′-(3-methoxypropyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-219);-   (R)-N-hydroxy-5′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-220);-   (R)-N-hydroxy-5′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-221);-   (S)-N-hydroxy-1′-(3-methoxypropyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-222);-   (S)-N-hydroxy-5′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-223);-   (S)-N-hydroxy-5′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-224);-   (R)-N-hydroxy-1′-(2-methylbenzyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-225);-   (R)-N-hydroxy-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-226);-   (R)-1′-(4-fluorophenyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-227);-   (R)-N-hydroxy-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-228);-   (R)-N-hydroxy-5′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide    (I-229);-   N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-230);-   N-hydroxy-2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-231);-   1′-benzyl-N-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-232);-   N-hydroxy-2′-oxo-1′-(pyridin-3-yl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-233);-   N-hydroxy-2′-oxo-1′-((tetrahydro-2H-pyran-4-yl)methyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-234);-   N-hydroxy-1′-isopropyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-235);-   N-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-236);-   N-hydroxy-1′-methyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide    (I-237);-   N-hydroxy-2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-238);-   1-benzyl-N-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-239);-   N-hydroxy-2-oxo-1-(pyridin-3-yl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-240);-   N-hydroxy-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-241);-   N-hydroxy-2-oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-242);-   N-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-243); and-   N-hydroxy-1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-244).

In one or more embodiments, the compound of Formula II can be selectedfrom:

-   N-hydroxy-1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]-6-carboxamide    (II-1);-   1′-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide    (II-2);-   1′-(cyclohexanecarbonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide    (II-3);-   N-hydroxy-1′-(4-methoxybenzoyl)spiro[chromane-2,4′-piperidine]-6-carboxamide    (II-4);-   N-hydroxy-1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide    (II-5);-   1′-(cyclohexylsulfonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide    (II-6);-   N6-hydroxy-N1′-phenylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxamide    (II-7);-   1′-cyclohexyl-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide    (II-8); and-   N-hydroxy-1′-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide    (II-9).

In one or more embodiments, the compound of Formula I can be selectedfrom:

-   N-hydroxy-1′-methyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-245);-   N-hydroxy-1-methyl-3′,4′-dihydro-1′H-spiro[azepane-3,2′-naphthalene]-6′-carboxamide    (I-246);-   N-hydroxy-1-methyl-3′,4′-dihydro-1′H-spiro[azocane-3,2′-naphthalene]-6′-carboxamide    (I-247);-   N-hydroxy-1-methyl-2-oxo-3′,4′-dihydro-1′H-spiro[azepane-3,2′-naphthalene]-6′-carboxamide    (I-248);-   N-hydroxy-1-methyl-2-oxo-3′,4′-dihydro-1′H-spiro[azocane-3,2′-naphthalene]-6′-carboxamide    (I-249);-   N-hydroxy-1′-methyl-6′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide    (I-250);-   N-hydroxy-1-methyl-7-oxo-3′,4′-dihydro-1′H-spiro[azepane-3,2′-naphthalene]-6′-carboxamide    (I-251);-   N-hydroxy-1-methyl-8-oxo-3′,4′-dihydro-1′H-spiro[azocane-3,2′-naphthalene]-6′-carboxamide    (I-252);-   N-hydroxy-1′-methyl-2′-oxospiro[chromane-2,3′-piperidine]-6-carboxamide    (I-253);-   N-hydroxy-1-methyl-2-oxospiro[azepane-3,2′-chromane]-6′-carboxamide    (I-254);-   N-hydroxy-1-methyl-2-oxospiro[azocane-3,2′-chromane]-6′-carboxamide    (I-255);-   N-hydroxy-1-methyl-2-oxospiro[piperidine-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-256);-   N-hydroxy-1-methyl-2-oxospiro[azepane-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-257); and-   N-hydroxy-1-methyl-2-oxospiro[azocane-3,2′-thiochromane]-6′-carboxamide    1′,1′-dioxide (I-258).

In one embodiment of the compounds of Formulae I and II, Y¹, Y³, and Y⁴are each CR¹. In other embodiments, Y¹ is N and Y³ and Y⁴ are each CR¹.In other embodiments, Y³ is N and Y¹ and Y⁴ are each CR¹. In otherembodiments, Y⁴ is N and Y¹ and Y³ are each CR¹.

In some embodiments of the compounds of Formulae I and II, Y¹, Y³, andY⁴ are each CR¹ and X¹, X², X³, X⁴, X⁵, X⁶, and X⁷ are eachindependently —CR¹R²—. In some embodiments, X¹ is —C(O)—, and X², X³,X⁴, X⁵, X⁶, and X⁷ are each independently —CR¹R²—. In some embodiments,X² is —C(O)—, and X¹, X³, X⁴, X⁵, X⁶, and X⁷ are each independently—CR¹R²—. In some embodiments, X³ is —C(O)—, and X¹, X², X⁴, X⁵, X⁶, andX⁷ are each independently —CR¹R²—. In some embodiments, X⁴ is —C(O)—,and X¹, X², X³, X⁵, X⁶, and X⁷ are each independently —CR¹R²—. In someembodiments, X⁵ is —C(O)—, and X¹, X², X³, X⁴, X⁶, and X⁷ are eachindependently —CR¹R²—. In some embodiments, X⁶ is —C(O)—, and X¹, X²,X³, X⁴, X⁵, and X⁷ are each independently —CR¹R²—. In some embodiments,X⁷ is —C(O)—, and X¹, X², X³, X⁵, X⁵, and X⁶ are each independently—CR¹R²—.

In other embodiments of the compounds of Formulae I and II, X¹ is —NR³—,and X², X³, X⁴, X⁵, X⁶, and X⁷ are each independently —CR¹R²—. In someembodiments, X² is —NR³—, and X¹, X³, X⁴, X⁵, X⁶, and X⁷ are eachindependently —CR¹R²—. In some embodiments, X³ is —NR³—, and X¹, X², X⁴,X⁵, X⁶, and X⁷ are each independently —CR¹R²—. In some embodiments, X⁴is —NR³—, and X¹, X², X³, X⁵, X⁶, and X⁷ are each independently —CR¹R²—.In some embodiments, X⁵ is —NR³—, and X¹, X², X³, X⁴, X⁶, and X⁷ areeach independently —CR¹R²—. In some embodiments, X⁶ is —NR³—, and X¹,X², X³, X⁴, X⁵, and X⁷ are each independently —CR¹R²—. In someembodiments, X⁷ is —NR³—, and X¹, X², X³, X⁴, X⁵, and X⁶ are eachindependently —CR¹R²—.

In other embodiments of the compounds of Formula I, X¹ is —O—, —SO₂—,—S(O)—, or —S—, and X², X³, X⁴, X⁵, X⁶, and X⁷ are each independently—CR¹R²—. In some embodiments, X² is —O—, —SO₂—, —S(O)—, or —S—, and X¹,X³, X⁴, X⁵, X⁶, and X⁷ are each independently —CR¹R²—. In someembodiments, X³ is —O—, —SO₂—, —S(O)—, or —S—, and X¹, X², X⁴, X⁵, X⁶,and X⁷ are each independently —CR¹R²—. In some embodiments, X⁴ is —S—,—SO₂— or —S(O)—, and X¹, X², X³, X⁵, X⁶, and X⁷ are each independently—CR¹R²—. In some embodiments, X⁵ is —S—, —SO₂— or —S(O)—, and X¹, X²,X³, X⁴, X⁶, and X⁷ are each independently —CR¹R²—. In some embodiments,X⁶ is —O—, —SO₂—, —S(O)—, or —S—, and X¹, X², X³, X⁴, X⁵, and X⁷ areeach independently —CR¹R²—. In some embodiments, X⁷ is —O—, —SO₂—,—S(O)—, or —S—, and X¹, X², X³, X⁴, X⁵, and X⁶ are each independently—CR¹R²—.

In other embodiments of the compounds of Formula II, X¹ is —O—, —SO₂—,—S(O)—, or —S—, and X², X³, X⁴, X⁵, X⁶, and X⁷ are each independently—CR¹R²—. In some embodiments, X² is —O—, —SO₂—, —S(O)—, or —S—, and X¹,X³, X⁴, X⁵, X⁶, and X⁷ are each independently —CR¹R²—. In someembodiments, X³ is —O—, —SO₂—, —S(O)—, or —S—, and X¹, X², X⁴, X⁵, X⁶,and X⁷ are each independently —CR¹R²—. In some embodiments, X⁴ is —O—,—SO₂—, —S(O)—, or —S—, and X¹, X², X³, X⁵, X⁶, and X⁷ are eachindependently —CR¹R²—. In some embodiments, X⁵ is —S—, —SO₂— or —S(O)—,and X¹, X², X³, X⁴, X⁶, and X⁷ are each independently —CR¹R²—. In someembodiments, X⁶ is —S—, —SO₂— or —S(O)—, and X¹, X², X³, X⁴, X⁵, and X⁷are each independently —CR¹R²—. In some embodiments, X⁷ is —O—, —SO₂—,—S(O)—, or —S—, and X¹, X², X³, X⁴, X⁵, and X⁶ are each independently—CR¹R²—.

In other embodiments of the compounds of Formulae I and II, L is a bond.In other embodiments, L is —(CR¹R²)_(n)—. In other embodiments, L is—S(O)₂—. In other embodiments, L is —S(O)₂NR³—, —S(O)—, or —S(O)NR³—. Inother embodiments, L is —C(O)(CR¹R²)_(n)O—. In other embodiments, L is—C(O)(CR¹R²)_(n)— and n is 0. In other embodiments, L is —C(O)NR³—.

In other embodiments of the compounds of Formulae I and II, R is—C₁-C₆alkyl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —CN, —R¹, —R², —SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹,—C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹,heterocycle, aryl, or heteroaryl. In other embodiments, R is—C₂-C₆alkenyl or —C₂-C₆alkynyl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —SR³, —OR³, —NHR³, —NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, or heteroaryl. In otherembodiments, R is aryl or heteroaryl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —SR³, —OR³, —NHR³, —NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, or heteroaryl. In otherembodiments, R is —C₄-C₈cycloalkenyl, —C₃-C₈cycloalkyl,—C₅-C₁₂spirocycle, heterocyclyl, or spiroheterocyclyl, optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R²,—SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, orheteroaryl.

In other embodiments of the compounds of Formula I, m is 0, 1, 2, or 3.In another embodiment m is 0. In yet another embodiment, m is 1. In yetanother embodiment, m is 2. In yet another embodiment, m is 3.

In some embodiments of the invention, the compounds of Formula I orFormula II are enantiomers. In some embodiments the compounds are the(S)-enantiomer. In other embodiments the compounds are the(R)-enantiomer. In yet other embodiments, the compounds of Formula I orFormula II may be (+) or (−) enantiomers. As used herein, a chemicalstructure that is labelled as “R/S” indicates that the structurerepresents one enantiomer, the stereochemistry of which is not defined.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration. All tautomeric formsare also intended to be included.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I or Formula II may be prepared by methodsknown in the art of organic synthesis as set forth in part by thefollowing synthetic schemes and examples. In the schemes describedbelow, it is well understood that protecting groups for sensitive orreactive groups are employed where necessary in accordance with generalprinciples or chemistry. Protecting groups are manipulated according tostandard methods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I or Formula II. Those skilled in the art willrecognize if a stereocenter exists in the compounds of Formula I orFormula II. Accordingly, the present invention includes both possiblestereoisomers (unless specified in the synthesis) and includes not onlyracemic compounds but the individual enantiomers and/or diastereomers aswell. When a compound is desired as a single enantiomer or diastereomer,it may be obtained by stereospecific synthesis or by resolution of thefinal product or any convenient intermediate. Resolution of the finalproduct, an intermediate, or a starting material may be affected by anysuitable method known in the art. See, for example, “Stereochemistry ofOrganic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994).

Preparation of Compounds

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the Formula I (e.g., Formula I-m, I-n, I-p,I-q, I-r and II-g) can be synthesized using the methods described below,together with synthetic methods known in the art of synthetic organicchemistry, or variations thereon as appreciated by those skilled in theart. These methods include but are not limited to those methodsdescribed below.

wherein L and R are defined as in Formula (I).

The general way of preparing target molecules of Formula (I-n) by usingintermediates 2a, 2b, 2c, 2d, and 2e is outlined in General Scheme 1.Hydrogenation of 2,6-dimethyl naphthalene-2,6-dicarboxylate (2a) in thepresence of palladium on carbon under standard conditions affords 2b.Deprotonation of 2b with a base, followed by alkylation with ahalo-nitrile provides intermediates 2c. Spiro-lactams 2d can be obtainedby treatment of 2c with platinum (IV) oxide (PtO₂) in the presence ofhydrogen (H₂) gas and ammonia (NH₃). Addition of the R-L moiety can beachieved via standard methods of alkylation or arylation. For example,alkylation of 2d with an alkyl halide in the presence of a base, e.g.sodium hydride, can provide compounds of intermediates 2e.Alternatively, arylation of 2d with an aryl bromide or aryl iodide inthe presence of a metal catalyst, e.g. copper (I) iodide (CuI), and abase, e.g. cesium carbonate (Cs₂CO₃), can also provide compounds ofintermediates 2e. Treatment of 2e with hydroxylamine and a base, e.g,sodium hydroxide, provides compounds of Formula (I-n).

The general way of preparing target molecules of Formula (I-p) by usingintermediates 2a, 2b, 2c, 2d, 2f, and 2g is also outlined in GeneralScheme 1. Spiro-amines 2f can be obtained by treatment of 2d withborane-tetrahydrofuran complex under standard reduction conditions.Addition of the R-L moiety can be achieved via standard methods ofalkylation, arylation, acylation, urea formation, or sulfonation.Treatment of 2g with hydroxylamine and a base, e.g, sodium hydroxide,provides compounds of Formula (I-p).

wherein L and R are defined as in Formula (I).

The general way of preparing target molecules of Formula (I-q) by usingintermediates 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, and 2p is outlined inGeneral Scheme 2. Treatment of 4-bromobenzenethiol (2h) with2,5-dihydrofuran-2,5-dione and a base, e.g. triethylamine, followed byaluminum chloride, affords 2i. Treatment of 2i with triethylsilane inthe presence of an acid, e.g. trifluoroacetic acid, provides 2j.Standard esterification methods afford methyl ester 2k. Carbonylation of2k with carbon monoxide gas in the presence of a metal catalyst, e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂), a base, e.g. triethylamine, and methanol, affords 2l.Deprotonation of 2l with a base, followed by alkylation with ahalo-nitrile provides intermediates 2m, which can be readily oxidized tothe sulfones 2n with m-chloroperoxybenzoic acid. Spiro-lactams 2o can beobtained by treatment of 2n with PtO₂ in the presence of H₂ gas and NH₃.Addition of the R-L moiety can be achieved via standard methods ofalkylation or arylation. For example, alkylation of 2o with an alkylhalide in the presence of a base, e.g. sodium hydride, can providecompounds of intermediates 2p. Alternatively, arylation of 2o with anaryl bromide or aryl iodide in the presence of a metal catalyst, e.g.palladium (II) acetate (Pd(OAc)₂), a ligand, e.g.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), and a base,e.g. Cs₂CO₃, can also provide compounds of intermediates 2p. Treatmentof 2p with hydroxylamine and a base, e.g, sodium hydroxide, providescompounds of Formula (I-q).

wherein L and R are defined as in Formula (I).

The general way of preparing target molecules of Formula (I-r) by usingintermediates 2q, 2r, 2s, 2t, 2u, 2v, and 2w is outlined in GeneralScheme 3. Nitrile addition to 6-bromo-3,4-dihydronaphthalen-2(1H)-one(2q), for example with trimethylsilyl cyanide in the presence of zincdiiodide, followed by dehydration, for example with phosphorus (V)oxychloride, provides 2r. Carbonylation of 2r with carbon monoxide gasin the presence of a metal catalyst, e.g. Pd(dppf)Cl₂, a base, e.g.triethylamine, and methanol, affords methyl ester 2s. Treatment of 2swith magnesium provides affords 2t, which can be deprotonated with abase, and alkylated with a halo-ester to provide intermediates 2u.Spiro-lactams 2v can be obtained by treatment of 2u with PtO₂ in thepresence of H₂ gas and NH₃. Addition of the R-L moiety can be achievedvia standard methods of alkylation or arylation. For example, alkylationof 2v with an alkyl halide in the presence of a base, e.g. sodiumhydride, can provide compounds of intermediates 2w. Alternatively,coupling of 2v with an aryl boronic acid in the presence of a metalcatalyst, e.g. copper (II) acetate (Cu(OAc)₂), and a base, e.g.triethylamine, can also provide compounds of intermediates 2w. Treatmentof 2w with hydroxylamine and a base, e.g, sodium hydroxide, providescompounds of Formula (I-r).

wherein L and R are defined as in Formula (I).

The general way of preparing target molecules of Formula (I-s) by usingintermediates 2x, 2y, 2z, 2aa, 2bb, and 2cc is outlined in GeneralScheme 4. Carbonylation of ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate(2x) can be achieved by treatment with carbon monoxide gas in thepresence of a metal catalyst, e.g. Pd(dppf)Cl₂, a base, e.g.triethylamine, and methanol, to afford methyl ester 2y. Reduction of thechromenone, for example by treatment with H₂ gas in the presence ofpalladium on carbon and acetic acid, provides chromane 2z. Deprotonationof 2z with a base, followed by alkylation with a halo-nitrile providesintermediates 2aa. Spiro-lactams 2bb can be obtained by treatment of 2aawith PtO₂ in the presence of H₂ gas and NH₃. Addition of the R-L moietycan be achieved via standard methods of alkylation or arylation. Forexample, alkylation of 2bb with an alkyl halide in the presence of abase, e.g. sodium hydride, can provide compounds of intermediates 2cc.Alternatively, coupling of 2bb with an aryl bromide or aryl iodide inthe presence of a metal catalyst, e.g. Pd(OAc)₂, a ligand, e.g.XantPhos, and a base, e.g. Cs₂CO₃, can also provide compounds ofintermediates 2cc. Treatment of 2cc with hydroxylamine and a base, e.g,sodium hydroxide, provides compounds of Formula (I-s).

wherein L and R are defined as in Formula (II).

The general way of preparing target molecules of Formula (II-f) by usingintermediates 2dd, 2ee, 2ff, 2gg, 2hh, 2ii, and 2jj is outlined inGeneral Scheme 5. Treatment of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one(2dd) with tert-butyl 4-oxopiperidine-1-carboxylate in the presence of abase affords 2ee, which can be reduced by stepwise treatment with sodiumborohydride, followed by triethylsilane and trifluroacetic acid toafford 2gg. Carbonylation of 2gg can be achieved by metal exchange, e.g.with n-butyl lithium, followed by treatment with methyl chloroformate,to afford methyl ester 2hh. Spiro-amine 2ii can be readily obtained bystandard Boc deprotection methods. Addition of the R-L moiety can beachieved via standard methods of alkylation, arylation, acylation, ureaformation, or sulfonation. Treatment of 2jj with hydroxylamine and abase, e.g, sodium hydroxide, provides compounds of Formula (II-f).

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease associated with HDAC6 modulation in a subject in need thereof.The method involves administering to a patient in need of treatment fordiseases or disorders associated with HDAC6 modulation an effectiveamount of a compound of Formula I or Formula II. In an embodiment, thedisease can be, but is not limited to, cancer, neurodegenerativedisease, neurodevelopmental disease, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, or cardiovasculardisease.

Another aspect of the invention is directed to a method of inhibitingHDAC6. The method involves administering to a patient in need thereof aneffective amount of Formula I or Formula II.

The present invention relates to compositions capable of modulating theactivity of (e.g., inhibiting) HDACs, and in particular HDAC6. Thepresent invention also relates to the therapeutic use of such compounds.

One therapeutic use of the compounds of the present invention is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include but is not limited to lung cancer, ovarian cancer, breastcancer, prostate cancer, pancreatic cancer, hepatocellular cancer, renalcancer and leukemias such as acute myeloid leukemia and acutelymphoblastic leukemia. Additional cancer types include T-cell lymphoma(e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma), Hodgkinlymphoma, melanoma and multiple myeloma. In other embodiments, treatingproliferative diseases or disorders can include any cancer where thereis evidence of an increase in Treg/effector T cell ratio or in anabsolute Treg number, either in the periphery or in the tumormicroenvironment or tertiary lymphoid structures, or increasedexpression of T cell tolerance-related genes. Such proliferativediseases or disorders can include but are not limited to: any Krasmutant carrying tumor(http://cancerimmunolres.aacrjournals.org/content/early/2016/02/13/2326-6066.CIR-15-0241.long);renal cell carcinoma; lung carcinoma; cervical cancer; prostate cancer;ovarian cancer; head and neck cancer; lymphoma; colorectal cancer,non-small cell lung carcinoma; breast cancers (Gobert, M. et al. (2009)Cancer Res. 69, 2000-2009); and bladder cancer.

One therapeutic use of the compounds of the present disclosure is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders orneurodegenerative diseases can include but are not limited to epilepsy,attention deficit disorder (ADD), Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma causedby tissue injury, oxidative stress-induced neuronal or axomaldegeneration, and multiple sclerosis.

Another therapeutic use of the compounds of the present disclosure is totreat neurodevelopmental disorders. Neurodevelopmental disorders caninclude, but are not limited to, Rett syndrome, intellectual disability,intellectual and developmental disability, autism spectrum disorder,fetal alcohol syndrome, developmental coordination disorder, stereotypicmovement disorder, Tourette syndrome, cerebral palsy, fragile Xsyndrome, attention deficit hyperactivity disorder, and Mendelsohnn'ssyndrome.

Another therapeutic use of the compounds of the present invention isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-10, andincreased expression of the FOXP3 transcription factor. In someembodiments, the inflammatory diseases include fibrosis or fibroticdiseases. Types of fibrotic diseases include but are not limited to lungfibrosis or pulmonary fibrosis, Liver fibrosis; Heart fibrosis;Mediastinal fibrosis; Retroperitoneal cavity fibrosis; Bone marrowfibrosis; Skin fibrosis; and Scleroderma or systemic sclerosis.

Another therapeutic use of the compounds of the present invention isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include but are not limited to rheumatoidarthritis, Crohn's disease, type-1 diabetes, systemic juvenileidiopathic arthritis; inflammatory bowel disease; allografttransplantation; eczema, psoriasis, idiopathic thrombocytopenic purpra,autoimmune thrombocytopenia, acquired immune thrombocytopenia,autoimmune neutropenia, autoimmune hemolyitic anemia, parvovirusB19-associated red cell aplasia, acquired antifactor VIII autoimmunity,acquired von Willebrand disease, monoclonal gammopathy, aplastic anemia,pure red cell aplasia, Diamond-Blackfan anemia, hemolytic disease of thenewborn, immune mediated-refractoriness to platelet transfusion,hemolytic uremic syndrome, Evan's syndrome, Guillain-Barre syndrome,chronic demyelinating polyradiculoneuropathy, paraproteinemic IgMdemyelinating polyneuropathy, Lamber-Eaton myasthenic syndrome,myasthenia gravis, multifocal motor neuropathy, stiff man syndrome,paraneoplastic encephalomyelitis, sensory neuropathy with anti-Huantibodies, myelitis, autoimmune diabetic neuropathy, acute idiopathicneuropathy, toxic epidermal necrolysis, gangrene, granuloma, pemphigusvulgaris, bullous pemphigoid, vitiligo, scleroderma, atomic dermatitis,systemic and diffuse sclerosis, primary biliary cirrhosis, Celiacdisease, dermatitis herpetiformis, cryptogenic cirrhosis, reactivearthritis, Hashimoto's thryroditis, Wegner's granulomoatosis,micropolyarterits, Churg-Strauss syndrome Type I and Type II autoimmunepolygalndular syndromes, linear IgA disease, epidermolysis bullosaacquisita, erythema nodosa, pemphigoid gestationis, cicatricialpemphigoid, mixed essential cryoglobulinemia, chronic bullous disease ofchildhood, Goodpasture's syndrome, sclerosis cholangitis, ankylosingspondylitis, Bechet's syndrome temporal arteritis, Takayasu's arteritis,autoimmune urticaria, and Kawasaki's disease.

Another therapeutic use of the compounds of the present invention isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus.Bacterial infections include, but are not limited to streptococcusinfections, mycobacterial infections, bacillus infections, Salmonellainfections, Vibrio infections, spirochete infections, and Neisseriainfections. Viral infections include, but are not limited to herpesvirus infections, hepatitis virus infections, west nile virusinfections, flavivrus infections, influenza virus infections, rhinovirusinfections, papillomavirus infections, paromyxovirus infections,parainfluenza virus infections, and retrovirus infections. In particularembodiments, the compounds of the present invention are useful fortreating infections which result in an inflammatory cytokine burst.Nonlimiting examples of such infections include Ebola and othe viralhemorghagic fever-causing viruses, and Malaria.

Another therapeutic use of the compounds of the present invention isalso to treat and/or prevent allergy and unwanted immune responsesassociated with allergy. A non-limiting list of allergies and relatedconditions includes, pollen allergy (e.g. Japanese Cedar Pollen), moldallergy, food allergies (including, but not limited to peanut, tree nut,milk, soy, gluten, and egg allergies), animal allergies (e.g. allergiesto dogs, cats, rabbits), dust mite allergy, atopic dermatitis, allergicrhinitis, allergic otitis, allergic asthma, dry eye, ocular allergy,allergic urticaria, contact dermatitis, anaphalaxis, eosinophilicesophagitis.

Yet another therapeutic use of the compounds of the present invention isalso to treat metabolic diseases or disorders. Metabolic diseases can becharacterized as abnormalities in the way that a subject stores energy.Metabolic disorders can include but are not limited to metabolicsyndrome, diabetes, obesity, high blood pressure, non-alcoholic fattyliver disease and heart failure.

Yet another therapeutic use of the compounds of the present invention isalso to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include but are not limitedto anemia, multiple myeloma, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present invention isalso to prevent and/or treat transplant rejection. Tissues that aretransplanted include (but are not limited to) whole organs such askidney, liver, heart, lung; organ components such as skin grafts and thecornea of the eye; and cell suspensions such as bone marrow cells andcultures of cells selected and expanded from bone marrow or circulatingblood, and whole blood transfusions.

Yet another therapeutic use of the compounds of the present invention isalso to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, Brain infarct after cerebral artery occlusion;atherosclerosis, peripheral artery disease, cardiac hypertrophy, cardiacarrhythmias, stroke, and heart failure.

Another therapeutic use of the compounds of the present invention is forpurging the reservoir of latently infected memory CD4+ T cells in HIV+patients (Matalon, et al., Mol Med. 2011; 17(5-6): 466-472).

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Another aspect of the present disclosure relates to a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, for use in treatingor preventing a disease associated with HDAC6 modulation. In someembodiments, the disease is cancer, neurodegenerative disease,neurodevelopmental disorder, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, or cardiovasculardisease. In some embodiments, the compound inhibits a histonedeacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In another aspect, the present disclosure relates to the use of acompound of Formula (I) or Formula (II), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, in the manufacture of a medicament for treating or preventing adisease associated with HDAC6 modulation. In some embodiments, thedisease is cancer, neurodegenerative disease, neurodevelopmentaldisorder, inflammatory or autoimmune disease, infection, metabolicdisease, hematologic disease, or cardiovascular disease. In someembodiments, the compound inhibits a histone deacetylase. In anotherembodiment, the compound inhibits a zinc-dependent histone deacetylase.In another embodiment, the compound inhibits the HDAC6 isozymezinc-dependent histone deacetylase.

In some embodiments, the cancer is melanoma, cutaneous T-cell lymphoma,peripheral T-cell lymphoma, Hodgkin lymphoma, multiple myeloma,leukemia, lung, ovarian, breast, prostate, pancreatic, hepatocellular orrenal cancer. In other embodiments, the neurodegenerative disease isAlzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis,or spinal muscular atrophy. In other embodiments, the neurodevelopmentaldisorder is Rett syndrome. In yet other embodiments, the inflammatory orautoimmune disease is rheumatoid arthritis, spondylitis arthritis,psoriatic arthritis, psoriasis, multiple sclerosis, systemic lupuserythematosus, inflammatory bowel diseases, graft versus host disease,transplant rejection or fibrotic disease.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a compound of the disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoylresidues. Furthermore, the disclosed compounds can be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug, for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels. In one embodiment, disclosed compoundsare not covalently bound to a polymer, e.g., a polycarboxylic acidpolymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of Formula I or Formula II and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier can furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present invention can inhibit HDACs such as HDAC6 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present invention includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, in particularHDAC6. For instance, the present invention features a unique class ofsmall molecule therapeutic agents of Formula I or Formula II. Thecompounds were designed by using crystal structure information of HDACligand-protein complexes as well as advanced computational chemistrytools. These techniques led to the development of new chemical scaffoldsthat were iteratively refined to optimize key recognition featuresbetween the ligand and receptor known to be necessary for potency.

Definitions used in the following examples and elsewhere herein are:

-   AcOH Acetic acid-   AlCl₃ Aluminum chloride-   CH₂Cl₂ Methylene chloride, Dichloromethane-   CH₃CN Acetonitrile-   CO (g) Carbon monoxide gas-   CH₃I Iodomethane-   CO₂ Carbon dioxide-   Cs₂CO₃ Cesium carbonate-   Cu(OAc)₂ Copper (II) acetate-   CuI Copper (I) iodide-   CuBr Copper (I) bromide-   DCE 1,2-Dichloroethane-   DMA Dimethylacetamide-   DIEA Diisopropylethylamine-   DMC 2-Chloro-1,3-dimethylimidazolinium chloride-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   Et₃N Triethylamine-   Et₂O Diethyl ether-   EtOAc Ethyl acetate-   EtOH Ethanol-   h hours-   H₂ (g) Hydrogen (gas)-   H₂O Water-   HB TU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium    hexafluorophosphate-   HCl Hydrochloric acid-   K₂CO₃ Potassium carbonate-   K₃PO₄ Potassium phosphate tribasic-   LDA Lithium diisopropylamide-   m-CPBA 3-Chloroperbenzoic acid-   MeOH Methanol-   MgSO₄ Magnesium sulfate-   min minutes-   NaBH(OAc)₃ Sodium triacetoxyborohydride-   Na₂CO₃ Sodium carbonate-   Na₂SO₄ Sodium sulfate-   NH₄Cl Ammonium chloride-   NH₄HCO₃ Ammonium bicarbonate-   NaH Sodium hydride-   NaHCO₃ Sodium bicarbonate-   NH₃ Ammonia-   NaI Sodium iodide-   NaOH Sodium hydroxide-   NH₂OH Hydroxylamine-   NMM 4-Methylmorpholine-   Pd(dppf)Cl₂    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(dppf)Cl₂.CH₂Cl₂    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane    adduct-   Pd(OAc)₂ Palladium (II) acetate-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   POCl₃ Phosphorus (V) oxychloride-   PtO₂ Platinum (IV) oxide-   PTSA p-Toluenesulfonic acid monohydrate-   RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl-   RuPhos Pd G2    Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)    [2-(2′-amino-1,1′-biphenyl)]palladium(II)-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TMSCN Trimethylsilyl cyanide-   XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene-   ZnI₂ Zinc diiodide

Example 1 Preparation of1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-176)

Step-1: Dimethyl 1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 2-L pressure tank reactor was placed 2,6-dimethylnaphthalene-2,6-dicarboxylate (50 g, 204.71 mmol, 1 equiv) inisopropanol (1.2 L), palladium on carbon (9.5 g) and acetic acid (5 g,83.26 mmol, 0.41 equiv). Hydrogen gas (50 atm) was introduced. Theresulting solution was stirred for 2 days at 40° C. The solids werefiltered off. The filter cake was washed with 2×200 mL of CH₂Cl₂ and2×200 mL of MeOH. The combined filtrate was concentrated under vacuum.The residue was dissolved with 300 mL of EtOAc. The pH was adjusted to 8using aq. Na₂CO₃. The organic layer was washed with 3×100 mL of H₂O anddried with anhydrous Na₂SO₄, filtered and concentrated under vacuum togive 40 g (79% yield) of the title compound as a white solid. MS: (ES,m/z): 249 [M+H]⁺.

Step-2: Dimethyl2-(2-cyanoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 500-mL 3-necked round-bottom flask purged and maintained with N₂,was placed dimethyl 1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (6g, 24.17 mmol, 1 equiv) in THF (50 mL, 1 equiv). The solution was cooledto −78° C. and LDA (2M in THF/hexanes, 24.2 mL 2 equiv) was addeddropwise to the stirring solution. After 30 min, 3-bromopropanenitrile(4.8 g, 35.83 mmol, 1.5 equiv) was added at −78° C. The resultingsolution was stirred for additional 2 h. The reaction was then quenchedby the addition of 30 mL of NH₄Cl. The resulting solution was extractedwith 3×20 mL of EtOAc. The combined extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby normal phase chromatography on silica gel with EtOAc/petroleum ether(1/1). The collected fractions were concentrated to give 1.6 g (22%yield) of the title compound as a white solid. MS: (ES, m/z): 302[M+H]⁺.

Step-3: Methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into a 250-mL 3-necked round-bottom flask was placed dimethyl2-(2-cyanoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (1.6 g,5.31 mmol, 1 equiv) in MeOH (50 mL), PtO₂ (0.4 g) and NH₃/MeOH (8 mL).To the above mixture, H₂ (g) was introduced and the resulting mixturewas stirred for 16 h at room temperature under H₂ atmosphere. The solidswere filtered out and the filtrate was concentrated under vacuum. Thecrude product was purified by re-crystallization from EtOAc. Thisprovided 1 g (69% yield) of the title compound as an off-white solid.MS: (ES, m/z): 274 [M+H]⁺.

Step-4: Methyl1′-benzyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into a 100-mL round-bottom flask was placed methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(100 mg, 0.37 mmol, 1 equiv) in DMF (5 mL, 1 equiv). The resultingmixture was cooled to 0° C. in an ice-water bath. NaH (60% dispersion inoil, 29.3 mg, 1.22 mmol, 3 equiv) was added and the mixture stirred at0° C. for 30 min. Then (bromomethyl)benzene (68.4 mg, 0.40 mmol, 1.1equiv) was added to the reaction. The resulting mixture was stirred for1h at room temperature. The reaction was then quenched by the additionof 10 mL of water and was extracted with 3×10 mL of EtOAc. The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentratedunder vacuum to give 120 mg (90% yield) of the title compound as ayellow solid. MS: (ES, m/z): 364[M+H]⁺.

Step-5:1′-Benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 50-mL round-bottom flask was placed methyl1′-benzyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(120 mg, 0.33 mmol, 1 equiv), THF/MeOH (4:1, 2 mL), NH₂OH (50% in water,326.7 mg, 30 equiv), and 1N aq. NaOH (26.4 mg, 2 equiv). The resultingsolution was stirred for 1h at room temperature. The pH of the solutionwas adjusted to 6 with 1N aq. HCl. The crude product was purified byPrep-HPLC with the following conditions: Column: Waters HSS C18, 2.1×50mm, 1.8 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05%TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2.0 min, hold 0.6min; Detector: UV 254 nm. The collected fractions were lyophilized togive 18.1 mg (15% yield) of the title compound as a pink solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.09 (s, 1H), 7.51 (s, 1H), 7.46-7.48 (d,J=8 Hz, 1H), 7.34-7.38 (m, 2H), 7.21-7.29 (m, 3H), 7.14-7.16 (d, J=8 Hz,1H), 4.53 (s, 2H), 3.15-3.25 (m, 3H), 2.70-2.80 (m, 3H), 2.08-2.18 (m,1H), 1.74-1.77 (m, 3H), 1.58-1.61 (m, 2H). MS: (ES, m/z): 365[M+H]⁺.

Example 2 Preparation ofN-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-177)

Into an 8-mL vial, was placed a solution of methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(70 mg, 0.26 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL), NH₂OH (50% inwater, 0.51 mL, 2 equiv) and 1N aq. NaOH (0.51 mL, 30 equiv). Theresulting solution was stirred for 3 h at room temperature. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:Sunfire C18, 19×150, 5 μm; Mobile Phase A: Water/0.05% TFA, Mobile PhaseB: CH₃CN/0.05% TFA; Flow rate: 25 mL/min; Gradient: 5% B to 52% B in 6min); Detector: UV 254 nm, 220 nm. The collected fractions werelyophilized to give 39.2 mg (56% yield) of the title compound as anoff-white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.08 (br s, 1H),7.50-7.41 (m, 3H), 7.13-7.12 (m, 1H), 3.16-3.06 (m, 3H), 2.82-2.71 (m,2H), 2.70-2.65 (m, 1H), 2.08-2.00 (m, 1H), 1.70-1.66 (m, 3H), 1.59-1.58(m, 2H). MS: (ES, m/z): 275 [M+H]⁺.

Example 3 Preparation ofN-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-178)

Step-1:1′-Methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylicacid

Into an 8-mL vial, was placed a solution of methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(100 mg, 0.37 mmol, 1 equiv) in DMF (4 mL). This was followed by theaddition of NaH (60% dispersion in oil, 44 mg, 1.83 mmol, 3 equiv), inportions at 0° C. over 10 min. To this was added CH₃I (104 mg, 0.73mmol, 2 equiv). The resulting mixture was stirred for 18 h at roomtemperature. The reaction was then quenched by the addition of 10 mL ofNH₄Cl (aq.) at 0° C. The resulting solution was extracted with 2×20 mLof EtOAc. The aqueous layers were combined and the pH of the solutionwas adjusted to 4 with 1N aq. HCl. The resulting solution was extractedwith 3×30 mL of CH₂Cl₂, dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum to give 137.6 mg (crude) of the titlecompound as a light yellow oil which was used in the next step withoutpurification. MS: (ES, m/z): 274 [M+H]⁺.

Step-2:N-Hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into an 8-mL vial, was placed a solution of1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylicacid (135 mg, 0.49 mmol, 1 equiv) in DMA (3 mL). This was followed bythe addition of isopropyl chloroformate (311 mg, 2.47 mmol, 5 equiv) andNMM (250 mg, 2.47 mmol, 5 equiv) at 0° C. over 10 min. To this was addeda solution of NH₂OH.HCl (173 mg, 2.47 mmol, 5 equiv) in DMA (1.5 mL).The resulting solution was stirred for 18 h at room temperature. Thecrude product was purified by Prep-HPLC with the following conditions:Column: Sunfire C18, 5 μm, 19×100 mm; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 25 mL/min; Gradient: 5% B to52% B in 6 min; Detector: UV 254 nm, 220 nm. The collected fractionswere lyophilized to give 46.4 mg (33% yield) of the title compound as anoff-white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.08 (br s, 1H),7.50-7.45 (m, 2H), 7.12-7.10 (d, J=8.0 Hz, 1H), 3.32-3.25 (m, 2H),3.11-3.07 (m, 1H), 2.83 (s, 3H), 2.79-2.69 (m, 2H), 2.66-2.62 (m, 1H),2.10-2.02 (m, 1H), 1.79-1.78 (m, 2H), 1.74-1.63 (m, 1H), 1.62-1.53 (m,2H). MS: (ES, m/z): 289 [M+H]⁺.

Example 4 Preparation of(R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-179) and(S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-180)

Step-1: Methyl1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into an 8-mL vial, was placed a solution of methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(100 mg, 0.37 mmol, 1 equiv) in DMF (4 mL). This was followed by theaddition of NaH (60% dispersion in oil, 44 mg, 1.83 mmol, 3 equiv), inportions at 0° C. over 10 min. To this was added CH₃I (104 mg, 0.73mmol, 2 equiv). The resulting solution was stirred for 18 h at roomtemperature. The reaction was then quenched by the addition of 10 mL ofNH₄Cl (aq.). The resulting solution was extracted with 3×30 mL ofCH₂Cl₂. The organic layers were combined, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum to provide 137.6 mg(crude) of the title compound as a light yellow oil. MS: (ES, m/z): 288[M+H]⁺.

Step-2: Chiral separation of the racemate to obtain methyl(R)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateand methyl(S)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

The racemate of methyl1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(137.6 mg, 47.9 mmol, 1 equiv) was purified by Prep-SFC with thefollowing conditions: Column: Chiralpak IC 2×25 cm, 5 μm; Mobile PhaseA: Hexanes, Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 25% Bin 26 min; Detector: UV 254 nm, 220 nm. The first peak (Rt 18.65 min)was collected and concentrated to give 60 mg of a yellow solid which wasassigned as the R isomer of methyl1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate.MS: (ES, m/z): 288 [M+H]⁺. The second peak (Rt 22.25 min) was collectedand concentrated to give 40 mg of a yellow solid which was assigned asthe S isomer of methyl1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate.MS: (ES, m/z): 288 [M+H]⁺.

Step-3:(R)-N-Hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into an 8-mL vial, was placed a solution of the first eluted isomer fromStep 2, which was assigned as methyl(R)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (60 mg, 0.21 mmol, 1 equiv) in THF/MeOH (4:1, 1.5mL), NH₂OH (50% in water, 0.41 mL, 30 equiv) and 1N aq. NaOH (0.42 mL, 2equiv). The resulting solution was stirred for 2 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile PhaseA: Water/0.1% Formic Acid, Mobile Phase B: CH₃CN/0.1% Formic Acid; Flowrate: 20 mL/min; Gradient: 5% B to 40% B in 8 min; Detector: UV 254 nm,220 nm. The collected fractions were lyophilized to give 38.7 mg (64%yield) of the title compound as an off-white solid. ¹H-NMR (400 MHz,DMSO-d6) δ (ppm): 11.08 (br s, 1H), 8.94 (br s, 1H), 7.50-7.45 (m, 2H),7.12-7.10 (m, 1H), 3.32-3.25 (m, 2H), 3.12-3.07 (m, 1H), 2.83-2.2.79 (m,3H), 2.78-2.76 (m, 2H), 2.74-2.72 (m, 1H), 2.10-2.02 (m, 1H), 1.79-1.73(m, 2H), 1.69-1.61 (m, 1H), 1.59-1.51 (m, 2H). MS: (ES, m/z): 289[M+H]⁺.

Step-4:(S)-N-Hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into an 8-mL vial, was placed a solution of the second eluted isomerfrom Step 2, which was assigned as methyl(S)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (40 mg, 0.14 mmol, 1 equiv) in THF/MeOH (4:1, 1.5mL), NH₂OH (50% in water, 0.27 mL, 30 equiv) and 1N aq. NaOH (0.29 mL, 2equiv). The resulting solution was stirred for 2 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile PhaseA: Water/0.1% Formic Acid, Mobile Phase B: CH₃CN/0.1% Formic Acid; Flowrate: 20 mL/min; Gradient: 5% B to 40% B in 8 min; Detector: UV 254 nm,220 nm. The collected fractions were lyophilized to give 33.7 mg (84%yield) of the title compound as an off-white solid. ¹H-NMR (400 MHz,DMSO-d6) δ (ppm): 11.06 (br s, 1H), 8.92 (br s, 1H), 7.48-7.43 (m, 2H),7.10-7.08 (m, 1H), 3.31-3.25 (m, 2H), 3.10-3.06 (m, 1H), 2.81-2.61 (m,6H), 2.08-2.00 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.64 (m, 1H), 1.57-1.50(m, 2H). MS: (ES, m/z): 289 [M+H]⁺.

Example 5 Preparation of(R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-181) and(S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-182)

Step-1: Methyl2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into a 25-mL round-bottom flask, was placed methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate(500 mg, 1.83 mmol, 1 equiv) in DMSO (8 mL), iodobenzene (448 mg, 2.20mmol, 1.2 equiv), CuI (70 mg, 0.37 mmol, 0.2 equiv), Cs₂CO₃ (1.78 g,5.46 mmol, 3 equiv), and methyl[2-(methylamino)ethyl]amine (65 mg, 0.74mmol, 0.4 equiv). The resulting mixture was stirred overnight at 130° C.The reaction was then quenched by the addition of 20 mL of water,extracted with 3×50 mL of CH₂Cl₂, washed with 100 mL of brine, driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by normal phase column chromatography on silica gelwith EtOAc/petroleum ether (1:5). The collected fractions wereconcentrated under vacuum to give 150 mg (23% yield) of the titlecompound as an off-white solid. MS: (ES, m/z): 350 [M+H]⁺.

Step-2: Chiral separation of methyl(R)-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateand methyl(S)-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

The racemate was purified by Chiral-HPLC with the following conditions:Column: CHIRALPAK IC 2×25 cm, 5 μm; Mobile Phase A: Hexanes, MobilePhase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 21 min;Detector: UV 254 nm, 220 nm. The first eluting isomer (Rt 12.37 min) wascollected and concentrated under vacuum to give 55 mg (37% yield) of anoff-white solid which was assigned as the R isomer of methyl2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate.MS: (ES, m/z): 350 [M+H]⁺. The second eluting isomer (Rt 15.78 min) wascollected and concentrated under vacuum to give 48 mg (32% yield) of anoff-white solid which was assigned as the S isomer of methyl2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate.MS: (ES, m/z): 350 [M+H]⁺.

Step-3:(R)-N-Hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 25-mL round-bottom flask, was placed the first eluted isomer fromStep 2, which was assigned as methyl(R)-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (55 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 3 mL),NH₂OH (50% in H₂O, 1560 mg, 30.56 mmol, 150 equiv) and 1N aq. NaOH (0.3mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered out and the crude product waspurified by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.01% NH₄HCO₃,Mobile Phase B: CH₃CN; Gradient: 15% B to 60% B in 6 min; Detector: UV254 nm, 220 nm. The collected fractions were lyophilized to give 38.6 mg(70% yield) of the title compound as an off-white solid. ¹H-NMR (300MHz, DMSO-d6) δ(ppm): 10.56 (s, 1H), 8.95 (s, 1H), 7.52-7.47 (t, J=8.3Hz, 2H), 7.41-7.36 (m, 2H), 7.27-7.22 (m, 3H), 7.16-7.14 (d, J=8 Hz,1H), 3.66-3.62 (t, J=5.9 Hz, 2H), 3.19-3.14 (d, J=16.8 Hz, 1H),2.88-2.73 (m, 3H), 2.18-2.08 (m, 1H), 1.96-1.70 (m, 5H). MS: (ES, m/z):351 [M+H]⁺.

Step-4:(S)-N-Hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 25-mL round-bottom flask, was placed the second eluted isomerfrom Step 2, which was assigned as methyl(S)-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (43 mg, 0.12 mmol, 1 equiv), THF/MeOH (4:1, 2 mL),NH₂OH (50% in H₂O, 1220 mg, 23.90 mmol, 150 equiv), 1N aq. NaOH (0.25mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered out and the crude product waspurified by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.01% NH₄HCO₃,Mobile Phase B: CH₃CN; Gradient: 15% B to 60% B in 6 min; Detector: UV254 nm, 220 nm. The collected fractions were lyophilized to give 39.4 mg(91% yield) of the title compound as an off-white solid. ¹H-NMR (400MHz, DMSO-d6) δ (ppm): 11.07 (br s, 1H), 8.97 (s, 1H), 7.53 (s, 1H),7.50-7.48 (d, J=8 Hz, 1H), 7.42-7.38 (t, J=7.8 Hz, 2H), 7.28-7.24 (m,3H), 7.17-7.15 (d, J=8 Hz, 1H), 3.67-3.64 (t, J=6 Hz, 2H), 3.19-3.15 (d,J=16.8 Hz, 1H), 2.88-2.75 (m, 3H), 2.18-2.09 (m, 1H), 1.96-1.84 (m, 3H),1.79-1.66 (m, 2H). MS: (ES, m/z): 351 [M+H]⁺.

Example 6 Preparation of(R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-185)

Step-1: Chiral separation of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateand methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

5 g of the racemate methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylatewas purified by Prep-SFC with the following conditions: Column:CHIRALPAK IA-SFC-02, 5 cm×25 cm; Mobile Phase A: CO₂: 50%, Mobile PhaseB: MeOH/CH₂Cl₂ (1:1) 50%; Flow rate: 180 mL/min; Detector: UV 220 nm.The first eluting isomer (Rt 3.53 min) was collected and concentratedunder vacuum to give 2.4 g (29% yield) of a white solid which wasassigned as the R isomer of methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas a white solid. MS: (ES, m/z): 274 [M+H]+. The second eluting isomer(Rt 4.49 min) was collected and concentrated under vacuum to give 2.4 g(29% yield) of a white solid which was assigned as the S isomer ofmethyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas a white solid. MS: (ES, m/z): 274 [M+H]+.

Step-2: Methyl(R)-1′-(cyclobutylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into a 25-mL round-bottom flask, was placed the first eluted isomer fromStep 1, which was assigned as methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (120 mg, 0.44 mmol, 1 equiv) in DMF (5 mL). This wasfollowed by the addition of NaH (60% dispersion in oil, 70 mg, 2.92mmol, 4 equiv) at 0° C. The mixture was stirred for 30 min at roomtemperature. Then (bromomethyl)cyclobutane (262 mg, 1.76 mmol, 1 equiv)was added. The resulting solution was stirred for 5 h at roomtemperature. The reaction was then quenched by the addition of 20 mL ofwater, extracted with 3×30 mL of CH₂Cl₂, washed with 50 mL of brine,dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by normal phase column chromatography on silica gelwith EtOAc/petroleum ether (1:1). The collected fractions wereconcentrated under vacuum to give 60 mg (40% yield) of the titlecompound as a yellow oil. MS: (ES, m/z): 342 [M+H]⁺.

Step-3:(R)-1′-(Cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 10-mL sealed tube, was placed a solution of the product from Step2, which was assigned as methyl(R)-1′-(cyclobutylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (60 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 4 mL),NH₂OH (50% in H₂O, 1394 mg, 42.20 mmol, 120 equiv), 1N aq. NaOH (0.35mL, 2 equiv). The resulting solution was stirred for 2 h at 28° C. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column: XBridge Prep C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B:CH₃CN; Gradient: 5% B to 65% B in 8 min; Detector: UV 254 nm, 220 nm.The collected fractions were lyophilized to give 34.8 mg (58% yield) ofthe title compound as an off-white solid. ¹H-NMR (400 MHz, DMSO-d6), δ(ppm): 11.09 (s, 1H), 8.94 (s, 1H), 7.50-7.45 (t, J=18.8 Hz, 2H),7.13-7.11 (d, J=8 Hz, 1H), 3.45-3.40 (m, 1H), 3.32-3.25 (m, 3H),3.13-3.08 (d, J=20 Hz, 1H), 2.74-2.65 (m, 2H), 2.61-2.51 (m, 2H),2.08-2.06 (t, J=8 Hz, 1H), 1.99-1.96 (m, 2H), 1.85-1.80 (m, 2H),1.79-1.64 (m, 5H), 1.57-1.51 (m, 2H). MS: (ES, m/z): 343 [M+H]⁺.

TABLE 1 The following compounds were prepared according to the method ofExample 6 using the first eluted enantiomer from Step 1. Found (ES, m/z)Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-196

(300 MHz, DMSO-d6): 9.57 (s, 1H), 7.49-7.45 (t, J = 14.1 Hz, 2H), 7.12-7.09 (t, J = 8.1 Hz, 1H), 4.64-61 (t, J = 7.2 Hz, 2H), 4.37-4.31 (m,2H), 3.70- 3.51(m, 2H), 3.32-3.19 (m, 3H), 3.12- 3.06 (d, J = 16.5 Hz,1H), 2.76-2.71 (m, 2H), 2.65-2.60 ( d, J = 16.5 Hz, 1H), 2.08-2.00 (m,1H), 1.78-1.61 (m, 3H), 1.57-1.50 (m, 2H) 345 I-187

(300 MHz, DMSO-d6): 7.47-7.43 (t, J = 12 Hz, 2H), 7.13-7.10 (d, J = 7.8Hz, 1H), 3.63-3.32 (m, 6H), 3.30-3.27 (m, 3H), 3.23-3.14 (t, J = 13.7Hz, 1H), 2.89-2.76 (m, 2H), 2.71-2.66 (d, J = 16.8 Hz, 1H), 2.24-2.13(m, 1H), 1.89- 1.68 (m, 5H), 1.67-1.51 (m, 2H) 347 I-189

(400 MHz, DMSO-d6): 11.09 (s, 1H), 8.95 (s, 1H), 7.50 (s, 1H), 7.47-7.45(d, J = 8 Hz, 1H), 7.13-7.11 (d, J = 7.6 Hz, 1H), 3.32-3.26 (m, 2H),3.25-3.18 (m, 1H), 3.14-3.02 (m, 2H), 2.77-2.73 (t, J = 8.4 Hz, 2H),2.70-2.63 (d, J = 16.8 Hz, 1H), 2.12-2.04 (m, 1H), 1.99-1.92 (m, 1H),1.78-1.74 (m, 2H), 1.69-1.62 (t, J = 15.6 Hz, 1H), 1.60-1.52 (m, 2H),0.86-0.83 (t, J = 2.8 Hz, 6H) 331 I-191

(300 MHz, DMSO-d6): 11.07 (s, 1H), 8.94 (s, 1H), 7.50-7.44 (t, J = 15.3Hz, 2H), 7.12-7.10 (t, J = 8.1 Hz, 1H), 4.72-4.63 (m, 1H), 3.31-3.08 (m,3H), 2.77-2.60 (m, 3H), 2.12-2.01 (m, 1H), 1.69-1.48 (m, 5H), 1.06-1.04(d, J = 6.9 Hz, 6H) 317 I-194

(400 MHz, DMSO-d6): 11.08 (s, 1H), 8.92 (s, 1H), 7.48-7.43 (t, J = 9.6Hz, 2H), 7.11-7.09 (d, J = 7.6 Hz, 1H), 3.30-3.25 (m, 4H), 3.11-3.06 (d,J = 16.8 Hz, 1H), 2.77-2.60 (m, 3H), 2.08- 2.00 (m, 1H), 1.77-1.71 (m,2H), 1.66- 1.59 (m, 1H), 1.57-1.48 (m, 2H), 1.03- 1.00 (t, J = 7.2 Hz,3H) 303

TABLE 2 The following compounds were prepared according to the method ofExample 6, with the following modification: In Step 2, the second elutedproduct from Step 1 was used. Found (ES, m/z) Ex. Structure ¹H-NMR δ(ppm) [M + H]⁺ I-186

(300 MHz, DMSO-d6): 11.06 (s, 1H), 8.93 (s, 1H), 7.49-7.44 (m, 2H),7.12- 7.10 (m, 1H), 3.46-3.39 (m, 1H), 3.31- 3.24 (m, 3H), 3.12-3.07 (m,1H), 2.82- 2.71 (m, 2H), 2.64-2.50 (m, 2H), 2.27- 1.95 (m, 3H),1.87-1.60 (m, 7H), 1.57- 1.46 (m, 2H) 343 I-195

(400 MHz, DMSO-d6): 8.94 (br s, 1H), 7.49-7.45 (m, 2H), 7.11-7.09 (d, J= 7.6 Hz, 1H), 4.63-4.59 (m, 2H), 4.37-4.32 (m, 2H), 3.69-3.64 (m, 1H),3.58-3.52 (m, 1H), 3.27-3.19 (m, 3H), 3.11-3.06 (d, J = 16.8 Hz, 1H),2.80-2.73 (m, 2H), 2.64-2.60 (d, J = 16.4 Hz, 1H), 2.10-2.01 (m, 1H),1.75-1.72 (m, 2H), 1.70-1.61 (m, 1H), 1.58-1.54 (m, 2H) 345 I-188

(300 MHz, CD₃OD): 7.50-7.46 (m, 2H), 7.16-7.13 (m, 1H), 3.51-3.38 (m,6H), 3.33-3.31 (m, 3H), 3.26-3.21 (m, 1H), 2.91-2.83 (m, 2H), 2.75-2.70(m, 2H), 2.27-2.16 (m, 1H), 1.88-1.77 (m, 7H) 347 I-190

(300 MHz, DMSO-d6): 11.06 (br s, 1H), 8.93 (br s, 1H), 7.49-7.41 (m,2H), 7.13-7.10 (d, J = 8.10 Hz, 1H), 3.28- 3.14 (m, 3H), 3.08-3.01 (m,2H), 2.76- 2.61 (m, 3H), 2.12-1.90 (m, 2H), 1.78- 1.51 (m, 5H),0.92-0.82 (m, 6H) 331 I-192

(300 MHz, DMSO-d6): 11.07 (s, 1H), 8.93 (s, 1H), 7.49-7.44 (m, 2H),7.12- 7.10 (m, 1H), 4.72-4.62 (m, 1H), 3.31- 3.08 (m, 3H), 2.81-2.60 (m,3H), 2.12- 2.01 (m, 1H), 1.73-1.54 (m, 5H), 1.10- 1.00 (m, 6H) 317 I-184

(300 MHz, DMSO-d6): 11.04 (s, 1H), 8.94 (s, 1H), 7.50-7.45 (m, 2H),7.12- 7.10 (m, 1H), 3.32-3.25 (m, 4H), 3.13- 3.07 (m, 1H), 2.81-2.66 (m,2H), 2.60- 2.50 (m, 1H), 2.11-2.00 (m, 1H), 1.80- 1.58 (m, 5H),1.08-0.96 (m, 3H) 303

Example 7 Preparation of(R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-193)

Step-1: Methyl(R)-1′-cyclopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of O₂, was placed the first eluted isomer from Example 6,Step 1, which was assigned as methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (100 mg, 0.37 mmol, 1 equiv) in THF (5 mL), Cu(OAc)₂(80 mg, 0.44 mmol, 1 equiv), Et₃N (120 mg, 1.19 mmol, 3 equiv), pyridine(40 mg, 0.51 mmol, 1.5 equiv), and cyclopropylboronic acid (105 mg, 1.22mmol, 3 equiv). The resulting solution was stirred overnight at 60° C.The solids were filtered out and the filtrate was quenched by theaddition of 50 mL of water, extracted with 3×20 mL of CH₂Cl₂, washedwith 100 mL of brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by normal phasecolumn chromatography on silica gel with CH₂Cl₂/MeOH (10:1). Thecollected fractions were concentrated under vacuum to give 90 mg (78%yield) of the title compound as a yellow oil. MS: (ES, m/z): 314 [M+H]⁺.

Step-2:(R)-1′-Cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of the productfrom Step 1, which was assigned as methyl(R)-1′-cyclopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (70 mg, 0.22 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL),NH₂OH (50% in H₂O, 1771 mg, 53.62 mmol, 120 equiv), 1N aq. NaOH (5 mL, 2equiv). The resulting solution was stirred for 2 h at 28° C. The solidswere filtered out and the crude product was purified by Prep-HPLC withthe following conditions: Column: XBridge Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH₃CN; Flowrate: 20 mL/min; Gradient: 28% B to 39% B in 8 min; Detector: UV 254 nm,220 nm. The collected fractions were lyophilized to give 22.2 mg (32%yield) of the title compound as an off-white solid. ¹H-NMR (300 MHz,DMSO-d6) δ(ppm): 11.04 (s, 1H), 8.92 (s, 1H), 7.49-7.44 (t, J=14.4 Hz,2H), 7.12-7.09 (d, J=7.8 Hz, 1H), 3.31-3.18 (m, 2H), 3.10-3.05 (d,J=16.8 Hz, 1H), 2.75-2.59 (m, 4H), 2.08-1.98 (m, 1H), 1.73-1.58 (m, 3H),1.54-1.48 (m, 2H), 0.72-0.61 (m, 2H), 0.56-0.48 (m, 2H). MS: (ES, m z):315 [M+H]⁺.

TABLE 3 The following compound was prepared according to the method ofExample 7, with the following modification: In Step 1, the second elutedproduct from Example 6, Step 1 was used. Found (ES, m/z) Ex. Structure¹H-NMR δ (ppm) [M + H]⁺ I-183

(300 MHz, DMSO-d6): 11.06 (s, 1H), 8.96-8.89 (m, 1H), 7.52-7.40 (m, 2H),7.10 (d, J = 7.9 Hz, 1H), 3.20 (t, J = 6.1 Hz, 2H), 3.07 (d, J = 16.7Hz, 1H), 2.86-2.52 (m, 4H), 2.11-1.94 (m, 1H), 1.80-1.48 (m, 3H),1.47-1.40 (m, 2H), 0.75-0.58 (m, 2H), 0.57-0.42 (m, 2H) 315

Example 8 Preparation of(R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-197) and(S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-198)

Step-1: Dimethyl2-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 100-mL round-bottom flask, was placed dimethyl2-(2-cyanoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (250mg, 0.83 mmol, 1 equiv), MeOH (25 mL), AcOH (8 mL), and PtO₂ (135 mg).H₂ (g) was introduced into the flask. The resulting solution was stirredfor 1 h at 25° C. The solid was filtered out and the filtrate wasconcentrated under vacuum to give 200 mg (74% yield) of the titlecompound as a yellow oil. MS: (ES, m/z): 306 [M+H]⁺.

Step-2: Dimethyl2-(3-(cyclobutylamino)propyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 25-mL round-bottom flask, was placed dimethyl2-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (200mg, 0.65 mmol, 1 equiv) in CH₂Cl₂ (6 mL), AcOH (0.2 mL) andcyclobutanone (46 mg, 0.66 mmol, 1 equiv). The resulting solution wasstirred for 1 h at 28° C. Then NaBH(OAc)₃ (695 mg, 3.28 mmol, 5 equiv)was added. The resulting solution was allowed to stir for an additional2 h at 28° C. The reaction was then quenched by the addition of 15 mL ofwater. The solids were filtered out and the filtrate was extracted with3×30 mL of CH₂Cl₂, dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by normal phasecolumn chromatography on silica gel with EtOAc/petroleum ether (1:2).The collected fractions were concentrated under vacuum to give 97 mg(41% yield) of the title compound as an off-white solid. MS: (ES, m/z):360 [M+H]⁺.

Step-3: Methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Into a 20-mL pressure tank reactor, was placed a solution of dimethyl2-(3-(cyclobutylamino)propyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate(200 mg, 0.56 mmol, 1 equiv) in NH₃(g)/MeOH (7M, 10 mL). The resultingsolution was stirred overnight at 90° C. The reaction was then cooled toroom temperature and quenched by the addition of 15 mL of water. Theresulting solution was extracted with 3×30 mL of CH₂Cl₂, dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by normal phase column chromatography on silica gel withEtOAc/petroleum ether (1:1). The collected fractions were concentratedunder vacuum to give 80 mg (44% yield) of the title compound as a yellowoil. MS: (ES, m/z): 328 [M+H]⁺.

Step-4: Chiral separation of methyl(R)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateand methyl(S)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate

Methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylatewas separated by Chiral-Prep-HPLC with the following conditions: Column:Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A: hexanes, Mobile Phase B:isopropanol; Gradient: hold 30% B over 36 min; Detector: UV 254 nm, 220nm. The first eluting isomer (Rt 4.876 min) was collected andconcentrated under vacuum to give 32 mg (40% yield) of an off-whitesolid which was assigned as the R isomer of methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate.MS: (ES, m/z): 328 [M+H]⁺. The second eluting isomer (Rt 6.071 min) wascollected and concentrated under vacuum to give 33 mg (41% yield) of anoff-white solid which was assigned as the S isomer of methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylate.MS: (ES, m/z): 328 [M+H]⁺.

Step-5:(R)-1′-Cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 10-mL vial, was placed a solution of the first eluted isomer fromStep 4, which was assigned as methyl(R)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (30 mg, 0.09 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL),NH₂OH (50% in H₂O, 691 mg, 20.92 mmol, 120 equiv), and 1N aq. NaOH (0.2mL, 2 equiv). The resulting solution was stirred for 2 h at 28° C. Thesolids were filtered out and the crude product was purified by Prep-HPLCwith the following conditions: Column: XBridge Prep C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.01% NH₄HCO₃, Mobile Phase B: CH₃CN;Gradient: 5% B to 60% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to give 15.9 mg (53% yield) of thetitle compound as an off-white solid. ¹H-NMR (300 MHz, DMSO-d6), δ(ppm): 10.88 (s, 1H), 8.94-8.92 (d, J=5.4 Hz, 1H), 7.49-7.44 (t, J=7.2Hz, 2H), 7.11-7.08 (d, J=7.8 Hz, 1H), 4.81-4.75 (t, J=9 Hz, 1H),3.28-3.24 (t, J=6.6 Hz, 2H), 3.09-3.04 (d, J=16.5 Hz, 1H), 2.76-2.60 (m,3H), 2.17-1.97 (m, 5H), 1.76 (s, 2H), 1.66-1.58 (m, 3H), 1.54-1.42 (m,2H). MS: (ES, m/z): 329 [M+H]⁺.

Step-6:(S)-1′-Cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide

Into a 8-mL vial, was placed a solution of the second eluted isomer fromStep 4, which was assigned as methyl(S)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxylateas described above, (34 mg, 0.10 mmol, 1 equiv) in THF/MeOH (4:1, 2.0mL), NH₂OH (50% in water, 0.21 mL, 30 equiv) and 1N aq. NaOH (0.21 mL, 2equiv). The resulting solution was stirred for 1 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile PhaseA: Water/0.1% Formic acid; Mobile Phase B: CH₃CN; Flow rate: 20 mL/min;Gradient: 5% B to 64% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to give 19.5 mg (57% yield) oftitle compound as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm):11.05 (s, 1H), 8.92 (s, 1H), 7.45-7.43 (m, 2H), 7.10-7.08 (m, 1H),4.80-4.70 (m, 1H), 3.36-3.19 (m, 1H), 3.07-3.03 (d, J=16.7 Hz, 1H),2.75-2.59 (m, 3H), 2.14-1.96 (m, 5H), 1.74-1.71 (m, 2H), 1.64-1.56 (m,3H), 1.53-1.47 (m, 2H). MS: (ES, m/z): 329 [M+H]⁺.

TABLE 4 The following compounds were prepared according to the method ofExample 8. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-199

(300 MHz, DMSO-d6): 11.06 (s, 1H), 8.96 (s, 1H), 7.50-7.44 (t, J = 7.7Hz, 2H), 7.12-7.10 (d, J = 7.8 Hz, 1H), 4.81-4.75 (t, J = 7.8 Hz, 1H),3.22-3.07 (m, 3H), 2.81-2.61 (m, 3H), 2.12-2.01 (m, 1H), 1.72-1.53 (m,13H) 343 I-200

(300 MHz, DMSO-d6): 11.07 (s, 1H), 8.95 (s, 1H), 7.50-7.44 (t, J = 8 Hz,2H), 7.12-7.10 (d, J = 8.1 Hz, 1H), 4.81-4.76 (d, J = 7.2 Hz, 1H),3.22-3.07 (m, 3H), 2.77-2.61 (m, 3H), 2.12-2.01 (m, 1H), 1.72-1.51 (m,13H) 343

Example 9 Preparation of1′-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-5)

Step-1: Dimethyl2-(cyanomethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 1-L 3-necked round-bottom flask was placed dimethyl1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (20 g, 80.56 mmol, 1equiv) in THF (400 mL). This was followed by the dropwise addition ofLDA (2 M in THF, 53 mL, 106 mmol, 1.32 equiv) with stirring at −78° C.over 30 min. To this was added 2-bromoacetonitrile (9 mL, 129 mmol, 1.6equiv) dropwise with stirring at −78° C. over 30 min. The resultingmixture was stirred overnight at room temperature. The reaction wasquenched by adding 300 mL of H₂O. The resulting solution was extractedwith 3×300 mL of EtOAc. The combined organics were washed with 2×300 mLof H₂O, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by normal phase chromatography on silica gel withEtOAc/petroleum ether (3:20). The collected fractions were concentratedto give 14 g (60% yield) of the title compound as a yellow oil. ¹H NMR(300 MHz, CDCl₃) δ (ppm): 7.83 (dq, J=3.5, 1.7 Hz, 2H), 7.20 (d, J=8.4Hz, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.42 (d, J=16.9 Hz, 1H), 3.06-2.83(m, 3H), 2.69 (s, 2H), 2.39-2.23 (m, 1H), 2.15-2.00 (m, 1H).

Step-2: Dimethyl2-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 1000-mL 3-necked round-bottom flask was placed dimethyl2-(cyanomethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (14 g,48.73 mmol, 1 equiv) in MeOH (440 mL), acetic acid (220 mL) and PtO₂ (6g). Hydrogen gas was introduced. The resulting solution was stirredovernight at room temperature. The solids were filtered out. The filtercake was washed with 2×100 mL of MeOH and 100 mL of CH₂Cl₂. The combinedfiltrate was concentrated under vacuum. The residue was dissolved in 200mL of EtOAc and the pH was adjusted to 9 with aq. Na₂CO₃. The resultingsolution was extracted with 3×200 mL of EtOAc. The combined organicswere dried over anhydrous Na₂SO₄, filtered and concentrated under vacuumto give 10 g (70% yield) of the title compound as a yellow oil. MS: (ES,m/z): 292 [M+H]⁺.

Step-3: Methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 500-mL round-bottom flask was placed dimethyl2-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (10 g,34.32 mmol, 1 equiv) in MeOH (80 mL) and NH₃ (7M in MeOH, 40 mL). Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum to give 9.1 g (crude) ofthe title compound as a solid. ¹H-NMR (300 MHz, CDCl₃) δ (ppm): 7.81 (s,1H), 7.78 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.01 (s, 1H), 3.90(s, 3H), 3.41-3.37 (t, J=6.6 Hz, 2H), 3.16-2.65 (m, 4H), 2.14-1.78 (m,4H). MS: (ES, m/z): 260 [M+H]⁺.

Step-4: Methyl1′-(1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(150 mg, 0.58 mmol, 1 equiv), 2-bromo-1H-1,3-benzodiazole (171 mg, 0.87mmol, 1.5 equiv), CuI (220 mg, 1.16 mmol, 2 equiv), K₃PO₄ (492 mg, 2.32mmol, 4.01 equiv), 1-N, 2-N-dimethylcyclohexane-1,2-diamine (124 mg,0.87 mmol, 1.51 equiv), and DMF (3 mL). The resulting solution wasdegassed three times with N₂, and stirred overnight at 100° C. Thereaction was quenched by adding 50 mL of H₂O. The resulting solution wasextracted with 3×50 mL of EtOAc. The organic layers were combined, driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by normal phase chromatography on silica gel withEtOAc/petroleum ether (1:9). The collected fractions were concentratedto give 63 mg (29% yield) of the title compound as a yellow oil. MS:(ES, m/z): 376 [M+H]⁺.

Step-5:1′-(1H-Benzo[d]imidazol-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 50-mL round-bottom flask was placed methyl1′-(1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(63 mg, 0.17 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 498 mg, 15.08 mmol, 89.85 equiv), and 1N aq. NaOH (0.5 mL, 2.94equiv). The resulting solution was stirred for 2 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge C18, 19×150 mm; Mobile phase A: Water/0.05%TFA, Mobile Phase B: CH₃CN/0.05% TFA; Gradient: 19% B to 51% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized togive 23.6 mg (37% yield) of the title compound as a pink solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.11 (br s, 1H), 7.56-7.50 (m, 4H),7.22-7.15 (m, 3H), 4.08-4.05 (t, J=6 Hz, 2H), 3.05-2.88 (m, 4H),2.19-1.93 (m, 4H). MS: (ES, m/z): 377 [M+H]⁺.

Example 10 Preparation ofN-hydroxy-1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-4)

Step-1: Methyl1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 10 mL microwave vial was added methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(50.2 mg, 0.194 mmol, 1 equiv) and 1-(2-bromoethyl)-4-methoxybenzene(45.8 mg, 0.213 mmol, 1.1 equiv) in DMF (1.5 mL). Next, sodiumbis(trimethylsilyl)amide (1M in THF, 0.25 mL, 1.3 equiv) was added andthe mixture was heated in the microwave at 150° C. for 20 min. Water wasadded and the reaction mixture was extracted with three portions ofEtOAc. The organic phases were combined, washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography on silica gel (Biotage SP1, 10 g Snap column,10-50% EtOAc/hexanes) to afford 15.8 mg (21% yield) of the titlecompound as a colorless oil. MS: (ES m/z) 394 [M+H]⁺.

Step-2:N-hydroxy-1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Methyl1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(20 mg, 0.051 mmol, 1 equiv) was dissolved in a solution of THF/MeOH(4:1, 1.38 mL). NH₂OH (50% in water, 0.279 mL, 4.6 mmol, 90 equiv) wasadded followed by 2N aq. NaOH (0.076 mL, 3 equiv). The reaction wasstirred at room temperature for 48 h and was purified directly byreverse-phase chromatography using the following conditions: Column:XTerra Prep MS C18 OBD, 5 mM, 19×100 mm; Mobile Phase A: Water/0.05%Formic Acid, Mobile Phase B: CH₃CN/0.05% Formic Acid; Flow rate: 20mL/min; Gradient: 15% B to 85% B in 10 min; Detector: UV 254 nm, 220 nm.Combined fractions were lyophilized to afford 6.2 mg (31% yield) thetitle compound. ¹H NMR (300 MHz, DMSO-d6) δ (PPM): 11.10 (br s, 1H),8.97 (br s, 2H), 7.34-7.54 (m, 2H), 6.97-7.29 (m, 3H), 6.86 (d, J=8.5Hz, 2H), 3.73 (s, 3H), 3.30-3.52 (m, 4H), 3.10-3.30 (m, 2H), 2.62-2.97(m, 4H), 1.47-1.85 (m, 4H). MS: (ES m/z) 395 [M+H]⁺.

Example 11 Preparation of1′-(3,4-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-6)

Step-1: Methyl1′-(3,4-dichlorobenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask was placed methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(150 mg, 0.58 mmol, 1 equiv), DMF (5 mL), NaH (29 mg, 1.21 mmol, 2.09equiv), and 4-(bromomethyl)-1,2-dichlorobenzene (193 mg, 0.80 mmol, 1.39equiv). The resulting solution was stirred for 3 h at room temperature.The resulting mixture was quenched with 30 mL of H₂O and extracted with2×50 mL of EtOAc. The combined organics were washed with 2×30 mL of H₂O,dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by normal phase chromatography on silica gel withEtOAc/petroleum ether (1:3). The collected fractions were concentratedto give 277 mg (crude) of the title compound as a yellow solid. MS: (ES,m/z): 418 [M+H]⁺.

Step-2:1′-(3,4-Dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 100-mL round-bottom flask was placed methyl1′-(3,4-dichlorobenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(277 mg, 0.66 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 4.57 g, 68.55 mmol, 104 equiv), and 1N aq. NaOH (1 mL, 1.51equiv). The resulting solution was stirred for 5 h at room temperature.The pH of the solution was adjusted to 6 with 4N aq. HCl. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:SunFire Prep C18, 5 μm, 19×100 mm; Mobile Phase A: Water/10% NH₄HCO₃,Mobile Phase B: CH₃CN/10% NH₄HCO₃; Gradient: 10% B to 50% B in 6 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized togive 30.2 mg (10% yield) of the title compound as a pink solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.10 (br s, 1H), 8.96 (br s, 1H), 7.65-7.63(d, J=8 Hz, 1H), 7.53-7.44 (m, 3H), 7.26-7.12 (m, 2H), 4.43 (s, 2H),3.27-3.24 (t, J=8 Hz, 2H), 2.95-2.77 (m, 3H), 2.67-2.61 (m, 1H),1.95-1.82 (m, 2H), 1.73-1.63 (m, 2H). MS: (ES, m/z): 419 [M+H]⁺.

TABLE 5 The following compounds were prepared according to the method ofExample 11. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-8

(400 MHz, DMSO-d6): 11.09 (br s, 1H), 9.12-8.78 (br s, 1H), 7.53-7.46(m, 2H), 7.18-7.11 (m, 5H), 4.37( s, 2H), 3.20-3.16 (t, J = 8 Hz, 2H),2.93-2.76 (m, 3H), 2.62-2.58 (m, 1H), 2.33 (s, 3H), 1.92-1.83 (m, 2H),1.71-1.63 (m, 2H). 365 I-7

(400 MHz, DMSO-d6): 11.09 (br s, 1H), 7.51-7.45 (m, 2H), 7.15-7.13 (d, J= 8 Hz, 1H), 3.32-3.29 (t, J = 4 Hz, 2H), 3.06-3.04 (d, J = 8 Hz, 2H),2.91- 2.74 (m, 3H), 2.62-2.55 (m, 1H), 1.91- 1.78 (m, 2H), 1.71-1.57 (m,7H), 1.27- 1.11 (m, 3H), 0.92-0.83 (m, 2H). 357 I-9

(300 MHz, DMSO-d6): 11.10 (br s, 1H), 10.28-9.82 (m, 2H), 9.05-8.95 (br,1H), 7.54-7.44 (m, 2H), 7.15-7.12 (d, J = 9 Hz, 1H), 3.37-3.27 (m, 4H),3.02- 2.96 (m, 2H), 2.96-2.83 (m, 3H), 2.77 (s, 6H), 2.68-2.59 (m, 1H),1.96-1.59 (m, 6H). 346

Example 12 Preparation of(R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-171) and(S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-172)

Step-1: Dimethyl2-(2-(cyclobutylamino)ethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate

Into a 250-mL round-bottom flask, was placed a mixture of 2,6-dimethyl2-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate (2 g,6.86 mmol, 1 equiv) and cyclobutanone (433.3 mg, 6.18 mmol, 0.9 equiv)in CH₂Cl₂ (50 mL) and AcOH (1 mL). The mixture was stirred for 15 min at0° C. After that NaBH(OAc)₃ (4.37 g, 20.58 mmol, 3 equiv) was slowlyadded at 0° C. The resulting solution was stirred overnight while thetemperature warmed to room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was purified bynormal phase chromatography on silica gel with CH₂Cl₂/MeOH (92:8). Thecollected fractions were concentrated to give 800 mg (34% yield) of thetitle compound as a light yellow oil. MS: (ES, m/z): 346 [M+H]⁺.

Step-2: Methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of dimethyl2-(2-(cyclobutylamino)ethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate(700 mg, 2.03 mmol, 1 equiv) and 7M NH₃ in MeOH (20 mL, 8 equiv). Theresulting solution was stirred for 18 h at 25° C. The resulting mixturewas concentrated under vacuum. The residue was purified by normal phasecolumn chromatography on silica gel column with EtOAc/petroleum ether(1:5). The collected fractions were concentrated to give 300 mg (47%yield) of the title compound as a light yellow oil. MS: (ES, m/z): 314[M+H]⁺.

Step-3: Chiral separation of methyl(R)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateand methyl(S)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

The racemate of methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(300 mg) was purified by Prep-SFC with the following conditions: Column:Chiralpak AS-H 2×25 cm; Mobile Phase A: CO₂ (70%), Mobile Phase B:isopropanol (30%); Flow rate: 40 mL/min; Detector: UV 220 nm. The firsteluting isomer (Rt 4.22 min) was collected and concentrated to give 120mg of a white solid which was tentatively assigned as the R isomer ofmethyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate.MS: (ES, m/z): 314 [M+H]⁺. The second eluting isomer (Rt 6.06 min) wascollected and concentrated to give 130 mg of a white solid which wastentatively assigned as the S isomer of methyl1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate.MS: (ES, m/z): 314 [M+H]⁺.

Step-4:(R)-1′-Cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of the firsteluted isomer from Step 3, which was assigned as methyl(R)-1′-cyclobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (50 mg, 0.16 mmol, 1 equiv), NH₂OH (50% in water,1.2 mL, 120 equiv) and 1N aq. NaOH (0.32 mL, 2 equiv) in THF/MeOH (5:1,1.25 mL). The reaction was stirred for 5 h at 25° C. The resultingmixture was concentrated under vacuum. The residue was dissolved in 3 mLof THF and purified by Prep-HPLC with the following conditions: Column:XBridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1% Formicacid, Mobile Phase B: CH₃CN/0.1% Formic Acid; Gradient: 20% B to 38% Bin 8 min; Detector: UV 254 nm, 220 nm. The collected fractions werelyophilized to give 25 mg (50% yield) of the title compound as a whitesolid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.68-1.70 (m, 4H), 1.78-1.90(m, 2H), 2.00-2.01 (m, 2H), 2.04-2.24 (m, 2H), 2.59 (d, J=6 Hz, 1H),2.81 (d, J=12 Hz, 3H), 3.41 (t, J=12 Hz, 2H), 4.47-4.52 (m, 1H), 7.13(m, J=6 Hz, 1H), 7.46-7.51 (m, 2H), 8.95 (s, 1H), 11.10 (s, 1H). MS:(ES, m/z): 315 [M+H]⁺.

Step-5:(S)-1′-Cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

(S)-1′-Cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamidewas prepared according to the method of(R)-1′-Cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide.¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.56-1.69 (m, 4H), 1.70-1.86 (m, 2H),1.96-2.01 (m, 2H), 2.17-2.22 (m, 2H), 2.55-2.60 (m, 1H), 2.77-2.83 (m,3H), 3.33-3.39 (m, 2H), 4.46-4.49 (m, 1H), 7.11 (d, J=7.6 Hz, 1H),7.46-7.49 (m, 2H), 8.93 (br s, 1H), 11.09 (br s, 1H). MS: (ES, m/z): 315[M+H]⁺.

Example 13 Preparation of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateand methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Step-1: Chiral separation of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateand methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

The racemate of methyl2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(22 g, 75.51 mmol, 1 equiv) was purified by Prep-SFC with the followingconditions: Column: Chiralpak AS-H, 5×25 cm, 5 μm; Mobile Phase: CO₂(50%), MeOH:CH₂Cl₂ (2:1)/0.2% DIEA; Detector: UV 220 nm. The firsteluting isomer (Rt 6.56 min) was collected and concentrated to give 10 gof a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 7.74-7.64 (m, 3H),7.23 (d, J=8.0 Hz, 1H), 3.21 (t, J=6.8 Hz, 2H), 2.99-2.75 (m, 3H),2.71-2.62 (m, 1H), 1.93 (m, 1H), 1.87-1.59 (m, 3H). MS: (ES, m/z): 260[M+H]⁺. The second eluting isomer (Rt 8.26 min) was collected andconcentrated to give 10 g of a yellow solid. ¹H NMR (400 MHz, DMSO-d6)δ(ppm): 7.74-7.64 (m, 3H), 7.23 (d, J=8.0 Hz, 1H), 3.21 (t, J=6.8 Hz,2H), 2.98-2.75 (m, 3H), 2.71-2.62 (m, 1H), 1.93 (m, 1H), 1.87-1.59 (m,3H). MS: (ES, m/z): 260 [M+H]⁺.

Step-2: Determination of the Absolute Stereochemistry of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of the firsteluting isomer from Step 1 (400 mg, 1.54 mmol, 1 equiv) in DMF (5 mL).This was followed by the addition of NaH (124 mg, 5.17 mmol, 1.5 equiv)at 0° C. over 10 min. To this was added1-(bromomethyl)-4-methanesulfonylbenzene (572 mg, 2.30 mmol, 2 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for 2h at 0° C. in a water-ice bath. The reaction was then quenched by theaddition of 40 mL of water. The resulting solution was extracted with3×100 mL of EtOAc and the combined organic layers were concentrated. Theresidue was purified on a C18 column eluting with 45% CH₃CN/water/0.05%TFA to afford 501 mg (60% yield) of a single isomer of methyl1′-[(4-methanesulfonylphenyl)methyl]-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate.TFAas a white solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92-7.94 (dd, J=8Hz, 2H), 7.70-7.72 (m, 2H), 7.49-7.51 (dd, J=8 Hz, 2H), 7.23-7.25 (dd,J=8 Hz, 1H), 4.53 (s, 2H), 3.82 (s, 3H), 3.28-3.24 (t, J=8 Hz, 2H), 3.22(s, 3H), 2.92-2.97 (m, 2H), 2.80-2.89 (m, 1H), 2.70-2.74 (m, 1H),1.84-1.97 (m, 2H), 1.76-1.74 (m, 2H). MS: (ES, m/z): 428 [M+H]⁺. Asample was recrystallized from EtOAc/hexanes (˜1:1) and submitted forsmall molecule X-ray crystallography, which showed the material to bemethyl(R)-1′-[(4-methanesulfonylphenyl)methyl]-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(see Example 52). Thus, the first eluting isomer of Step 1 was assignedas methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateand the second eluting isomer of Step 1 was assigned as methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate.

Example 14 Preparation of(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-20)

Step-1: Methyl(R)-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask maintained with the atmosphere ofnitrogen, was placed methyl(R)-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(100 mg, 0.39 mmol, 1 equiv) in toluene (5 mL), Pd₂(dba)₃ (7.9 mg, 0.01mmol, 0.02 equiv), XantPhos (66.0 mg, 0.11 mmol, 0.3 equiv), Cs₂CO₃(248.0 mg, 0.76 mmol, 1.97 equiv), and 2-bromopyridine (91.0 mg, 0.58mmol, 1.49 equiv). The resulting mixture was stirred overnight at 110°C. and then concentrated under vacuum. The residue was purified bynormal phase chromatography on silica gel with EtOAc/petroleum ether(1:5). The collected fractions were concentrated to give 40 mg (31%yield) of the title compound as a white solid. MS: (ES, m/z): 337[M+H]⁺.

Step-2:(R)-N-Hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 100-mL round-bottom flask was placed methyl(R)-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(40 mg, 0.12 mmol, 1 equiv) in THF/MeOH (4:1, 1.25 mL), NH₂OH (50% inwater, 786 mg, 23.8 mmol, 200 equiv) and 1N aq. NaOH (0.2 mL, 1.67equiv). The resulting solution was stirred for 4 h at room temperature.The resulting mixture was adjusted to pH 7 with 4N aq. HCl. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:X Bridge C18, 19×150 mm, 5 μm; Mobile Phase A: Water/0.05% TFA, MobilePhase B: CH₃CN/0.05% TFA; Flow rate: 28 mL/min; Gradient: 10% B to 40% Bin 7 min; Detector: UV 254 nm. The collected fractions were lyophilizedto give 36 mg (90% yield) of the title compound as a pink solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.10 (br s, 1H), 8.42-8.33 (m, 2H),7.86-7.82 (m, 1H), 7.55-7.49 (m, 2H), 7.18-7.15 (m, 2H), 4.03-3.96 (m,2H), 2.98-2.80 (m, 4H), 2.07-1.80 (m, 4H). MS: (ES, m/z): 338 [M+H]⁺.

TABLE 6 The following compounds were prepared according to the method ofExample 14. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-10

(400 MHz, DMSO-d6): 11.13 (s, 1H), 9.08 (s, 1H), 8.47-8.46 (d, J = 4.4MHz, 1H), 8.35-8.33 (d, J = 7.2 MHz, 1H), 7.66-7.49 (m, 3H), 7.23-7.11(m, 1H), 3.94-3.91 (t, J = 7.2 MHz, 2H), 2.98- 2.80 (m, 4H), 2.14-1.82(m, 4H). 338 I-16

(300 MHz, DMSO-d6): 11.14 (s, 1H), 8.78 (s, 2H), 8.19 (s, 2H), 7.56-7.50(m, 2H), 7.18-7.16 (d, J = 7.8 Hz, 1H), 4.02-3.97 (t, J = 6.9 Hz, 2H),3.01-2.84 (m, 4H), 2.18-2.11 (m, 1H), 2.09-1.92 (m, 3H). 338 I-26

(400 MHz, DMSO-d6): 11.10 (br s, 1H), 7.73-7.71 (d, J = 8 Hz, 2H), 7.58-7.38 (m, 4H), 7.18-7.12 (m, 2H), 3.88- 3.86 (t, J = 4 Hz, 2H), 2.97-2.78(m, 4H), 2.09-2.02 (m, 1H), 1.96-1.79 (m, 3H). 337

Example 15 Preparation of(R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-104)

Step-1: Methyl(R)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask was placed a solution of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(200 mg, 0.77 mmol, 1 equiv) in DMF (5 mL). NaH (60 mg, 2.50 mmol, 2equiv) was added in portions at 0° C. After stirring for 10 min,iodomethane (219 mg, 1.54 mmol, 2 equiv) was added dropwise at 0° C. Theresulting solution was stirred for 2.5 h at 0° C. The reaction wasquenched with 30 mL of water. The resulting solution was extracted 3×100mL with EtAOc. The organic layers were combined and concentrated underreduced pressure. The crude product was purified by normal phase columnchromatography on silica gel with EtOAc/petroleum ether (1:5). Thecollected fractions were concentrated to give 230 mg of the titlecompound as a yellow oil. MS: (ES, m/z): 274 [M+H]⁺.

Step-2:(R)-N-Hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 50-mL round-bottom flask was placed a solution of methyl(R)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(130 mg, 0.48 mmol, 1 equiv) in THF (2.0 mL), NH₂OH (50% in water, 1.87mL, 60 equiv) and 1N aq. NaOH (0.95 mL, 2 equiv). The resulting solutionwas stirred for 4 h at room temperature. The crude product was purifiedby Prep-HPLC with the following conditions: Column: X-bridge C18 190×50mm 5 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05%TFA; Gradient: 20% B to 60% B in 7 min; Detector: UV 254 nm. Thecollected fractions were lyophilized to give 43.5 mg (24% yield) of thetitle compound as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d6)δ(ppm): 11.09 (s, 1H), 8.95 (s, 1H), 7.45-7.51 (m, 2H), 7.11-7.13 (d,J=8 Hz, 1H), 3.28-3.32 (t, J=8 Hz, 2H), 2.76-2.89 (m, 6H), 2.50-2.56 (m,1H), 1.81-1.90 (m, 2H), 1.63-1.80 (m, 2H). MS: (ES, m/z): 275 [M+H]⁺.

TABLE 7 The following compounds were prepared according to the method ofExample 15, with the following modification: In Step 1, the halide canbe an iodide, a chloride, or a bromide. Found (ES, m/z) Ex. Structure¹H-NMR δ (ppm) [M + H]⁺ I-88

(400 MHz, DMSO-d6): 11.09 (s, 1H), 9.00 (s, 1H), 7.92-7.94 (dd, J = 8Hz, 2H), 7.46-7.52 (m, 4H), 7.15-7.17 (dd, J = 8 Hz, 1H), 4.54(s, 2H),3.22-3.28 (m, 5H), 2.81-2.95 (m, 3H), 2.65-2.70 (m, 1H), 1.86-1.97 (m,2H), 1.60-1.71 (m, 2H) 429 I-30

(400 MHz, DMSO-d6): 11.09 (s, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.45-7.47(dd, J = 8Hz, 1H), 7.13-7.15 (dd, J = 8 Hz, 1H), 4.60 (s, 2H), 3.29-3.22(t, J = 6.8 Hz, 2H), 2.79-2.90 (m, 3H), 2.50- 2.58 (m, 1H), 1.90-1.94(m, 1H), 1.80- 1.89 (m, 1H), 1.77-1.80 (m, 2H) 392 I-22

(400 MHz, DMSO-d6): 11.11 (br s, 1H), 7.79-7.72 (m, 2H), 7.532-7.37 (m,4H), 7.17-7.15 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.60 (s, 2H),3.70-3.67 (t, J = 6 Hz, 2H), 3.45-3.41 (t, J = 8 Hz, 2H), 3.24 (s, 3H),2.94-2.73 (m, 4H), 1.98- 1.72 (m, 4H) 449 I-14

(300 MHz, DMSO-d6): 11.14 (br s, 1H), 8.78-8.76 (d, J = 6 Hz 2H), 7.65-7.63 (d, J = 6 Hz, 2H), 7.56-7.48 (m, 2H), 7.18-7.15 (d, J = 9 Hz 1H),4.64 (s, 2H) 3.37-3.32 (t, J = 7.5 Hz, 2H), 2.96-2.70 (m, 4H), 2.04-1.72(m, 4H) 352 I-18

(300 MHz, DMSO-d6): 11.12 (br s, 1H), 8.71-8.67 (m, 2H), 8.04-8.01 (d, J= 9 Hz, 1H), 7.76-7.71 (m, 1H), 7.53- 7.42 (m, 2H), 7.16-7.13 (d, J = 9Hz, 1H), 4.56 (s, 2H), 3.32-3.28 (t, J = 6 Hz, 2H), 2.94-2.75 (m, 3H),2.70-2.64 (m, 1H), 1.98-1.81 (m, 2H), 1.77-1.60 (m, 2H) 352 I-24

(400 MHz, DMSO-d6): 11.08 (s, 1H), 7.51-7.46 (m, 2H), 7.15-7.09 (m, 1H),4.18-4.10 (m, 1H), 3.28-3.24 (t, 2H, J = 6.8 Hz), 2.89-2.60 (m, 4H),1.88-1.58 (m, 4H), 1.15-1.05 (m, 6H) 303  I-163

(400 MHz, DMSO-d6): 11.09 (s, 1H), 8.95 (s, 1H), 7.46-7.51 (m, 2H),7.12- 7.14 (d, J = 8.0 Hz, 1H), 4.31-4.35 (m, 1H), 3.27-3.32 (m, 2H),2.75-2.89 (m, 3H), 2.57-2.61 (m, 1H), 1.69-1.89 (m, 12H) 329  I-159

(400 MHz, DMSO-d6): 11.09 (br s, 1H), 8.95 (br s, 1H), 7.51 (s, 1H),7.47 (d, J = 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 2.32-2.29 (m, 2H),3.04-3.01 (m, 2H), 2.88-2.78 (m, 2H), 2.61 (d, J = 16 Hz, 1H), 1.93-1.78(m, 3H), 1.71-1.60 (m, 2H), 1.86 (d, J = 7 Hz, 6H) 317  I-161

(400 MHz, DMSO-d6): 11.08 (br s, 1H), 8.95 (br s, 1H), 7.51 (s, 1H),7.46 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 3.33-3.29 (m, 2H),3.27-3.23 (m, 2H), 2.89-2.75 (m, 3H), 2.59 (d, J = 17 Hz, 1H), 1.90-1.76(m, 2H), 1.70-1.65 (m, 2H), 1.05 (t, J = 8.0 Hz, 3H) 289  I-165

(400 MHz, DMSO-d6): 11.08 (s, 1H), 8.97 (s, 1H), 7.47-7.52 (m, 2H), 7.15(d, J = 8 Hz, 1H), 4.06-4.15 (m, 2H), 3.45-3.49 (m, 2H), 2.77-2.92 (m,3H), 2.66 (d, J = 16 Hz, 3H), 1.95-2.00 (m, 1H), 1.77-1.95 (m, 3H) 343

Example 16 Preparation of(R)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-12)

Step-1: Methyl(R)-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 10-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(60 mg, 0.23 mmol, 1 equiv),2-bromo-1-(2-methoxyethyl)-1H-1,3-benzodiazole (103 mg, 0.40 mmol, 1.5equiv) in toluene (4 mL), CuI (5 mg, 0.03 mmol, 0.1 equiv), Cs₂CO₃ (263mg, 0.81 mmol, 3 equiv), and (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (8 mg, 0.06 mmol, 0.2 equiv). Theresulting mixture was stirred for 10 h at 110° C. in an oil bath. Thereaction mixture was cooled to 20° C. with a water bath. The solids werefiltered out. The filtrate was concentrated under vacuum. The residuewas purified by normal phase chromatography on silica gel withEtOAc/petroleum ether (1:1). The collected fractions were concentratedto give 50 mg (50% yield) of the title compound as a colorless oil. MS:(ES, m/z): 434 [M+H]⁺.

Step-2:(R)-N-Hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 10-mL round-bottom flask was placed methyl(R)-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(50 mg, 0.12 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 0.5 mL, 63 equiv), and 1N aq. NaOH (0.3 mL, 2.5 equiv). Theresulting solution was stirred for 3 h at room temperature. The reactionmixture was cooled to 0° C. with an ice-water bath. The pH of thesolution was adjusted to 7 with 1N aq. HCl. The crude product waspurified by Prep-HPLC with the following conditions: Column: XBridgeC18, 19×150 mm, 5 μm; Mobile Phase A: Water/10% NH₄HCO₃, Mobile Phase B:CH₃CN/10% NH₄HCO₃; Flow rate: 25 mL/min; Gradient: 5% B to 47% B in 7min; Detector: UV 254 nm. The collected fractions were lyophilized togive 38.4 mg (77% yield) of the title compound as an off-white solid.¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.14 (br s, 1H), 7.65-7.48 (m, 4H),7.31-7.18 (m, 3H), 4.35-4.32 (t, J=6 Hz, 2H), 3.99-3.89 (m, 2H),3.62-3.59 (t, J=6 Hz, 2H), 3.20 (s, 3H), 3.01-2.86 (m, 4H), 2.22-2.16(m, 1H), 2.02-1.98 (m, 3H). MS: (ES, m/z): 435 [M+H]⁺.

Example 17 Preparation of(R)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-27)

Into a 50-mL round-bottom flask was placed a solution of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(100 mg, 0.39 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 1.52 mL, 60 equiv), and 1N aq. NaOH (0.77 mL, 2 equiv). Theresulting solution was stirred for 1.5 h at room temperature. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:Waters HSS C18, 2.1×50 mm, 1.8 μm; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% Bto 95% B in 2.0 min hold 0.6 min; Detector: UV 254 nm. The collectedfractions were lyophilized to give 40.6 mg (28% yield) of the titlecompound as a pink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.09 (s,1H), 8.94 (s, 1H), 7.66 (s, 1H), 7.45-7.50 (m, 2H), 7.13-7.15 (d, J=8Hz, 1H), 318-3.22 (t, J=7 Hz, 2H), 2.74-2.90 (m, 3H), 2.63-2.67 (m, 1H),1.90-1.95 (m, 1H), 1.68-1.80 (m, 2H), 1.60-1.64 (m, 1H). MS: (ES, m/z):261 [M+H]⁺.

Example 18 Preparation of(R)-N-hydroxy-1′-((2-hydroxythiazol-5-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-31)

Step-1: Methyl(R)-1′-((2-chlorothiazol-5-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask was placed a solution of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(250 mg, 0.96 mmol, 1 equiv) in DMF (5 mL). NaH (75 mg, 3.12 mmol, 2equiv) and 2-chloro-5-(chloromethyl)-1,3-thiazole (242 mg, 1.44 mmol,1.5 equiv) were added at 0° C. The resulting solution was stirred for2.5 h at 0° C. The residue was purified by reverse-phase purificationusing the following conditions: C18 column; Mobile Phase A: Water/0.05%TFA, Mobile Phase B: CH₃CN/0.05% TFA; Gradient: 50% B to 60% B;Detector: UV 254 nm. The collected fractions were lyophilized to give265 mg (54% yield) of the title compound as a light yellow oil. ¹H-NMR(400 MHz, CDCl₃) δ (ppm): 7.80-7.82 (m, 2H), 7.50 (s, 1H), 7.14-7.16(dd, J=8 Hz, 1H), 6.81 (s, 1H), 4.65 (s, 2H), 3.92 (s, 3H), 3.36-3.39(t, J=12 Hz, 2H), 3.12-3.16 (m, 1H), 2.98-3.06 (m, 1H), 2.82-2.90 (m,1H), 2.60-2.64 (m, 1H), 2.14-2.11 (m, 1H), 1.95-2.00 (m, 1H), 1.84-1.89(m, 1H), 1.70-1.76 (m, 1H). MS: (ES, m/z): 391 [M+H]⁺.

Step-2:(R)-N-Hydroxy-1′-((2-hydroxythiazol-5-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 50-mL round-bottom flask was placed a solution of methyl(R)-1′-((2-chlorothiazol-5-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(150 mg, 0.38 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 1.6 mL, 60 equiv) and 1N aq. NaOH (1.0 mL, 3 equiv). The reactionwas stirred for 6 h at room temperature. The crude product was purifiedby Prep-HPLC with the following conditions: Column: X-bridge C18 19×150mm, Mobile Phase A: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05% TFA;Gradient: 5% B to 70% B in 7 min; Detector: UV 254 nm. The collectedfractions were lyophilized to give 4.9 mg (4% yield) of the titlecompound as a pink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.02-11.09(m, 2H), 8.94 (s, 1H), 7.50-7.54 (m, 2H), 7.13-7.15 (d, J=8 Hz, 1H),6.84 (s, 1H), 4.30 (s, 2H), 3.23-3.26 (t, J=7.2 Hz, 2H), 2.80-2.89 (m,3H), 2.57-2.66 (m, 1H), 1.80-1.92 (m, 2H), 1.71-1.79 (m, 2H). MS: (ES,m/z): 374 [M+H]⁺.

Example 19 Preparation of(R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-109)

Step-1: Methyl(R)-1′-cyclopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A 4 mL vial with a Teflon screw-cap was charged with a solution ofmethyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(0.2M in 4:1 toluene/pyridine, 0.15 mL, 0.03 mmol, 1 equiv). ThenCu(OAc)₂ (11 mg, 0.06 mmol, 2 equiv) was added, followed by Cs₂CO₃ (20mg, 0.06 mmol, 2 equiv). Lastly a solution of2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2 M in toluene,0.3 mL, 0.6 mmol, 2 equiv) was added. The vial was purged with O₂ andsealed. The vial was heated at 110° C. for 72 h. Then reaction mixturewas then cooled to room temperature and diluted with 2 mL of EtOAc and 1mL of 1N aq. HCl. The vial was shaken and the organic layer wasseparated. The aqueous layer was extracted once more with 2 mL EtOAc.The combined organic layers were washed with brine and concentrated todryness. The title compound was carried forward as a residue withoutfurther purification. MS: (ES, m/z): 300 [M+H]⁺.

Step-2:(R)-1′-Cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a vial was placed methyl(R)-1′-cyclopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatein THF/MeOH (3:1, 0.2 mL), NH₂OH (50% in water, 0.15 mL, 76 equiv), and1N aq. NaOH (0.1 mL, 3.3 equiv). The reaction mixture was stirred atroom temperature for 4 h. The reaction mixture was concentrated andpurified by Prep-HPLC using the following conditions: Column: WatersSunfire C18, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% Formic Acid,Mobile Phase B: CH₃CN/0.1% Formic Acid; Flow rate: 23 mL/min; Gradient15% B to 100% B in 6 min; Detector: UV 254 nm, 220 nm. The collectedfractions were lyophilized to afford 4 mg (37% yield) of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.10 (s, 1H), 9.00 (s,1H), 7.67 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.13 (d, J=7.8 Hz,1H), 3.20 (t, J=8.0 Hz, 2H), 2.95-2.77 (m, 2H), 2.85 (d, J=16 Hz, 1H),2.66-2.61 (m, 2H), 1.95-1.89 (m, 1H), 1.83-1.69 (m, 2H), 1.66-1.60 (m,1H) 0.79-0.73 (m, 2H), 0.70-0.66 (m, 2H). MS: (ES, m/z): 301 [M+H]⁺.

Example 20 Preparation of(R)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-112)

Step-1:Methyl-(R)-1′-(3-cyanophenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A 7-mL vial with Teflon screw top and magnetic stir bar was charged withmethyl-(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(41 mg, 0.160 mmol, 1 equiv), Cs₂CO₃ (210 mg, 0.640 mmol, 4 equiv), anda solution of 3-bromobenzonitrile in 1,4-dioxane (0.2M, 0.880 mL, 0.176mmol, 1.1 equiv). The vial was sealed and brought into a nitrogen-filledglovebox where a solution of CuI and N,N′-dimethylethylenediamine in DMA(0.2M, 0.40 mL, 0.80 mmol, 0.5 equiv) was added. The vial was sealed andheated at 100° C. for 16 h. The reaction mixture was then cooled to roomtemperature and diluted with 30 mL of EtOAc and washed with sat. NH₄Cl(2×30 mL) and brine (1×30 mL). The organic phase was dried with Na₂SO₄,filtered and evaporated to dryness in vacuo to afford a pale yellowresidue which was carried forward without any further purification (51mg, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.07-8.05 (m, 1H),7.99-7.96 (m, 1H), 7.88-7.82 (m, 1H), 7.80-7.77 (m, 1H), 7.49 (t, J=8.2Hz, 1H), 7.41 (dt, J=7.8, 1.2 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 3.91, (s,3H), 3.86 (t, J=6.6 Hz, 2H), 3.20 (d, J=17 Hz, 1H), 3.12-3.05 (m, 1H),2.99-2.90 (m, 1H), 2.78 (d, J=17 Hz, 1H), 2.24-2.00 (m, 3H), 1.92-1.86(m, 1H). MS: (ES, m/z) 361 [M+H]⁺.

Step-2:(R)-1′-(3-Cyanophenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylicacid

Methyl-(R)-1′-(3-cyanophenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(51 mg, 0.140 mmol, 1 equiv) was dissolved in THF (1.0 mL). A solutionof LiOH in water (0.2 M, 1.0 mL, 0.200 mmol, 1.42 equiv) was added andthe reaction mixture stirred at room temperature for 16 h. The mixturewas diluted with 30 mL of EtOAc and 10 mL of 1M HCl. The layers wereseparated and the organic layer was evaporated to dryness in vacuo toafford a white solid. The solid was recrystallized from2-methyltetrahydrofuran/hexane (43 mg, 90% yield). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.04-8.00 (m, 2H), 7.92-7.87 (m, 2H), 7.52-7.43 (m, 2H),7.22 (d, J=7.8 Hz, 1H), 3.87 (t, J=6.6 Hz, 2H), 3.24 (d, J=17 Hz, 1H),3.12-3.05 (m, 1H), 2.99-2.90 (m, 1H), 2.80 (d, J=17 Hz, 1H), 2.24-2.00(m, 3H), 1.92-1.86 (m, 1H). MS: (ES, m/z): 347 [M+H]⁺.

Step-3:(R)-1′-(3-Cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

(R)-1′-(3-cyanophenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylicacid (10 mg, 0.030 mmol, 1 equiv) was dissolved in 0.150 mL of CH₃CN.N-methylmorpholine (0.011 mL, 0.100 mmol, 3.33 equiv) was added followedby propylphosphonic anhydride solution (50% by weight in EtOAc, 0.070mL, 7.8 equiv). The mixture stirred for 15 min at 50° C., then NH₂OH HCl(25 mg, 0.370 mmol, 12.33 equiv) was added. The mixture stirredvigorously at 50° C. for 48 h. The reaction mixture was then dilutedwith 3 mL of EtOAc and 2 mL of 1N aq HCl. The layers were separated andthe organic layer was washed with 1N aq HCl once more. The organic layerwas dried and the residue was purified by reverse-phase chromatographyPrep-HPLC using the following conditions: Column: Waters Sunfire C18, 5μm, 19×50 mm; Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B:CH₃CN/0.1% Formic acid; Gradient: 15% B to 100% B in 6 min; Flow rate:23 mL/min; Detector: UV 254 nm, 220 nm. The product containing fractionswere combined and concentrated to afford 0.6 mg (5.5% yield) of thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.10 (br s, 2H),8.04-8.00 (m, 2H), 7.92-7.87 (m, 2H), 7.52-7.43 (m, 2H), 7.22 (d, J=7.8Hz, 1H), 3.87 (t, J=6.6 Hz, 2H), 3.24 (d, J=17 Hz, 1H), 3.12-3.05 (m,1H), 2.99-2.90 (m, 1H), 2.80 (d, J=17 Hz, 1H), 2.24-2.00 (m, 3H),1.92-1.86 (m, 1H). MS: (ES, m/z): 362 [M+H]⁺.

TABLE 8 The following compound was prepared according to the method ofExample 20. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-175

(400 MHz, CDCl₃): 11.08 (br s, 1H), 8.91 (br s, 1H), 7.91 (s, 1H), 7.87(d, J = 8.2 Hz, 1H), 7.75 (d, J = 12 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H),7.48 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 3.97- 3.89 (m, 2H),3.30 (d, J = 17 Hz, 1H), 3.13-3.06 (m, 1H), 3.00-2.93 (m, 1H), 2.88 (d,J = 17 Hz, 1H), 2.27-2.04 (m, 3H), 2.00-1.94 (m, 1H) 362

TABLE 9 The following compounds were prepared according to the method ofExample 20, usingmethyl-(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatein Step 1. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-116

(400 MHz, CDCl₃): 11.08 (br s, 1H). 8.90 (br s, 1H), 8.04-8.00 (m, 2H),7.92-7.87 (m, 2H), 7.52-7.43 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H), 3.87 (t,J = 6.6 Hz, 2H), 3.24 (d, J = 17 Hz, 1H), 3.12- 3.05 (m, 1H), 2.99-2.90(m, 1H), 2.80 (d, J = 17 Hz, 1H), 2.24-2.00 (m, 3H), 1.92-1.86 (m, 1H)362 I-173

(400 MHz, CDCl₃): 8.13 (br s, 2H), 7.90-7.85 (m, 4H), 7.69-7.66 (m, 2H),7.20 (d, J = 7.8 Hz, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.23 (d, J = 17 Hz,1H), 3.11- 3.03 (m, 1H), 2.98-2.89 (m, 1H), 2.79 (d, J = 17 Hz, 1H),2.22-1.99 (m, 3H), 1.91-1.85 (m, 1H) 362 I-174

(400 MHz, CDCl₃): 11.08 (br s, 1H), 8.90 (br s, 1H), 7.91 (s, 1H), 7.87(d, J = 8.2 Hz, 1H), 7.75 (d, J = 12 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H),7.48 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 3.97- 3.89 (m, 2H),3.30 (d, J = 17 Hz, 1H), 3.13-3.06 (m, 1H), 3.00-2.93 (m, 1H), 2.88 (d,J = 17 Hz, 1H), 2.27-2.04 (m, 3H), 2.00-1.94 (m, 1H) 362

Example 21 Preparation of(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-21)

Step-1: Methyl(S)-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask maintained with the atmosphere ofnitrogen, was placed methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(100 mg, 0.39 mmol, 1 equiv) in toluene (5 mL), Pd₂(dba)₃ (7.9 mg, 0.01mmol, 0.02 equiv), XantPhos (66 mg, 0.11 mmol, 0.3 equiv), Cs₂CO₃ (250mg, 0.77 mmol, 1.99 equiv), and 2-bromopyridine (91 mg, 0.58 mmol, 1.49equiv). The resulting solution was stirred overnight at 110° C. Thesolids were filtered out. The residue was purified by normal phasechromatography on silica gel with EtOAc/petroleum ether (1:5). Thecollected fractions were concentrated to give 60 mg (46% yield) of thetitle compound as a white solid. MS: (ES, m/z): 337 [M+H]⁺.

Step-2:(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 100-mL round-bottom flask was placed methyl(S)-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(60 mg, 0.18 mmol, 1 equiv), THF/MeOH (4:1, 1.25 mL), NH₂OH (50% inwater, 1.18 g, 35.73 mmol, 60 equiv) and 1N aq. NaOH (0.4 mL, 2 equiv).The resulting solution was stirred for 5 h at room temperature. Theresulting mixture was adjusted to pH 7 with 4N aq. HCl. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:Waters HSS C18, 2.1×50 mm, 1.8 μm; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% Bto 95% B in 2.0 min, hold 0.6 min; Detector: UV 254 nm. The collectedfractions were lyophilized to give 33 mg (55% yield) of the titlecompound as a pink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.10 (s,1H), 8.42-8.33 (m, 2H), 7.86-7.82 (m, 1H), 7.55-7.49 (m, 2H), 7.18-7.15(m, 2H), 4.03-3.96 (m, 2H), 2.98-2.80 (m, 4H), 2.07-1.81 (m, 4H). MS:(ES, m z): 338 [M+H]⁺.

TABLE 10 The following compounds were prepared according to the methodof Example 21. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺I-11

(300 mHz, DMSO-d6): 11.13 (s, 1H), 9.09 (s, 1H), 8.47-8.46 (d, J = 4.4Hz, 1H), 8.35-8.32 (d, J = 7.2 Hz, 1H), 7.67-7.49 (m, 3H), 7.23-7.11 (m,1H), 3.94-3.91 (t, J = 7.2 Hz, 2H), 2.98-2.80 (m, 4H), 2.14-1.82 (m, 4H)338 I-17

(300 mHz, DMSO-d6): 11.14 (s, 1H), 8.77-8.75 (d, J = 9.9 Hz, 2H),8.18-8.15 (d, J = 6.9 Hz, 2H), 7.56-7.50 (m, 2H), 7.18-7.13 (m, 1H),4.01-3.97 (t, J = 6.9 Hz, 2H), 3.01-2.84 (m, 4H), 2.18-2.09 (m, 1H),1.98-1.91 (m, 3H) 338 I-29

(400 mHz, DMSO-d6): 11.14 (br s, 1H), 7.73-7.71 (d, J = 8 Hz, 2H), 7.55-7.36 (m, 4H), 7.20-7.12 (m, 2H), 3.88- 3.86 (t, J = 4 Hz, 2H), 2.97-2.78(m, 4H), 2.08-2.02 (m, 1H), 1.96-1.79 (m, 3H) 337

Example 22 Preparation of(S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-105)

Step-1: Methyl(S)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(100 mg, 0.39 mmol, 1 equiv) in DMF (5 mL). This was followed by theaddition of NaH (60% dispersion in oil, 30 mg, 1.25 mmol, 2 equiv) at 0°C. over 10 min. Then CH₃I (109 mg, 0.77 mmol, 2 equiv) was added at 0°C. The resulting mixture was stirred for 2.5 h at the same temperature.The reaction was then quenched by the addition of 30 mL of water. Theresulting solution was extracted with 3×80 mL of EtOAc. The organiclayers were combined and concentrated. The residue was purified bynormal phase chromatography on silica gel and eluted withEtOAc/petroleum ether (1:5). The collected fractions were concentratedto give 70 mg (66% yield) of the title compound as a yellow oil. MS:(ES, m/z): 274 [M+H]⁺.

Step-2:(S)-N-Hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 50-mL round-bottom flask, was placed a solution of methyl(S)-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(130 mg, 0.48 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), NH₂OH (50% inwater, 0.1.87 mL, 28.8 mmol, 60 equiv), and 1N aq. NaOH (0.95 mL, 0.95mmol, 2 equiv). The resulting solution was stirred for 4 h at roomtemperature. The crude product was purified by Prep-HPLC with thefollowing conditions: Column: XBridge C18, 19×150 mm, 5 μm; Mobile PhaseA: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 25mL/min; Gradient: 20% B to 60% B in 7.0 min; Detector: UV 254 nm. Thecollected fractions were lyophilized to give 47.7 mg (26% yield) of thetitle compound as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ(ppm): 11.09 (s, 1H), 8.95 (s, 1H), 7.45-7.51 (m, 2H), 7.11-7.13 (d, J=8Hz, 1H), 3.28-3.32 (t, J=8 Hz, 2H), 2.76-2.89 (m, 6H), 2.50-2.56 (m,1H), 1.81-1.91 (m, 2H), 1.65-1.80 (m, 2H). MS: (ES, m/z): 275 [M+H]⁺.

TABLE 11 The following compounds were prepared according to the methodof Example 22, with the following modification: In Step 1, the halidecan be an iodide, a chloride, or a bromide. Found (ES, m/z) Ex.Structure ¹H-NMR δ (ppm) [M + H ]⁺ I-23

(400 MHz, DMSO-d6): 11.12 (br s, 1H), 7.88-7.74 (m, 2H), 7.54-7.40 (m,4H), 7.16-7.14 (d, J = 8 Hz, 1H), 4.94- 4.89 (br, 2H), 4.64-4.56 (br,2H), 3.70 (s, 2H), 3.45-3.43 (t, J = 4 Hz, 2H), 3.24 (s, 3H), 2.94-2.79(m, 3H), 2.78- 2.66 (m, 1H), 2.01-1.69 (m, 4H) 449 I-15

(300 MHz, DMSO-d6): 11.14 (br s, 1H), 8.76-8.74 (d, J = 6 Hz, 2H), 7.62-7.60 (d, J = 6 Hz, 2H), 7.53-7.47 (m, 2H), 7.18-7.15 (d, J = 9 Hz 1H),4.62 (s, 2H), 3.36-3.32 (t, J = 6 Hz, 2H), 2.96-2.67 (m, 4H), 2.07-1.72(m, 4H) 352 I-19

(300 MHz, DMSO-d6): 11.11 (br s, 1H), 8.73-8.63 (m, 2H), 8.03-8.01 (d, J= 6 Hz, 1H), 7.75-7.71 (t, J = 6 Hz, 1H), 7.54-7.42 (m, 2H), 7.16-7.13(d, J = 9 Hz, 1H), 4.56 (s, 2H), 3.32-3.28 (t, J = 6 Hz, 2H), 2.94-2.81(m, 3H) 2.72- 2.63 (m, 1H), 1.98-1.81 (m, 2H), 1.77- 1.68 (m, 2H) 352I-25

(400 MHz, DMSO-d6): 11.09 (br s, 1H), 8.95 (br s, 1H), 7.53-7.45 (m,2H), 7.14-7.12 (d, J = 8 Hz, 1H), 4.18-4.11 (m, 1H), 3.27-3.23 (t, J = 8Hz, 2H), 2.92-2.76 (m, 3H), 2.62-2.54 (m, 1H), 1.88-1.68 (m, 2H),1.66-1.57 (m, 2H), 1.11-1.08 (m, 6H) 303 I-164

(400 MHz, DMSO-d6): 11.09 (s, 1H), 8.96 (s, 1H), 7.47 (d, J = 27 Hz,2H), 7.12 (d, J = 9 Hz, 1H), 4.29-4.36 (m, 1H), 329-3.34 (m, 2H),3.27-3.33 (m, 3H), 2.53 (d, J = 18 Hz, 1H), 1.68-1.89 (m, 12H) 329 I-160

(400 MHz, DMSO-d6): 11.08 (s, 1H), 8.96 (s, 1H), 7.43-7.50 (m, 2H), 7.15(d, J = 9 Hz, 1H), 3.29-3.34 (m, 2H), 3.03 (d, J = 6 Hz, 2H), 2.80-2.89(m, 3H), 2.51 (d, J = 3 Hz, 1H), 1.89-1.90 (m, 3H) 1.64-1.73 (m, 2H)0.85 (d, J = 15 Hz, 6H) 317 I-162

(400 MHz, DMSO-d6): 11.05 (m, 1H), 9.03 (m, 1H), 7.46-7.44 (m, 2H),7.12- 7.10 (m, 1H), 3.31-3.30 (m, 2H), 3.28- 3.20 (m, 2H), 2.88-2.78 (m,3H), 2.59- 2.49 (m, 1H), 1.89-1.76 (m, 2H), 1.74- 1.56 (m, 2H),1.04-1.01 (m, 3H) 289 I-166

(400 MHz, DMSO-d6): 11.03 (s, 1H), 7.50-7.44 (m, 2H), 7.14-7.11 (m, 1H),4.11-4.02 (m, 2H), 3.46-3.43 (m, 2H), 2.90-2.75 (m, 3H), 2.65-2.61 (m,1H), 1.97-1.91 (m, 1H), 1.85-1.70 (m, 2H), 1.66-1.63 (m, 1H) 343

Example 23 Preparation of(S)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-13)

Step-1: Methyl(S)-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 10-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(60 mg, 0.23 mmol, 1 equiv),2-bromo-1-(2-methoxyethyl)-1H-1,3-benzodiazole (103 mg, 0.40 mmol, 1.5equiv), CuI (5.0 mg, 0.03 mmol, 0.1 equiv), Cs₂CO₃ (263 mg, 0.81 mmol, 3equiv), toluene (2 mL), and (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (8 mg, 0.06 mmol, 0.2 equiv). Theresulting solution was stirred for 10 h at 110° C. in an oil bath. Thereaction mixture was cooled to 20° C. in a water bath. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was purified by normal phase chromatography on silica gel withEtOAc/petroleum ether (1:1). The collected fractions were concentratedto give 30 mg (30% yield) of the title compound as a yellow oil. MS:(ES, m/z): 434 [M+H]⁺.

Step-2:(S)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 10-mL round-bottom flask was placed methyl(S)-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(30 mg, 0.07 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 0.5 mL, 108 equiv), and 1N aq. NaOH (0.3 mL, 4.29 equiv). Theresulting solution was stirred for 3 h at room temperature. The reactionmixture was cooled to 0° C. in an ice-water bath. The pH of the solutionwas adjusted to 7 with 1N aq. HCl. The crude product was purified byPrep-HPLC with the following conditions: Column: X Bridge C18, 19×150mm, 5 μm; Mobile Phase A: Water/10% NH₄HCO₃, Mobile Phase B: CH₃CN/10%NH₄HCO₃; Flow rate: 25 mL/min; Gradient: 5% B to 47% B in 7.0 min;Detector: UV 254 nm. The collected fractions were lyophilized to give29.6 mg (98% yield) of the title compound as an off-white solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.14 (br s, 1H), 7.65-7.48 (m, 4H),7.28-7.17 (m, 3H), 4.35-4.33 (t, J=4 Hz, 2H), 3.99-3.89 (m, 2H),3.62-3.60 (t, J=4 Hz, 2H), 3.20 (s, 3H), 3.02-2.86 (m, 4H), 2.22-2.15(m, 1H), 2.02-1.97 (m, 3H). MS: (ES, m/z): 435 [M+H]⁺.

Example 24 Preparation of(S)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-28)

Into a 50-mL round-bottom flask was placed a solution of methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(100 mg, 0.39 mmol, 1 equiv) in THF/MeOH (4:1, 1.25 mL), NH₂OH (50% inwater, 1.52 mL, 60 equiv), and 1N aq. NaOH (0.77 mL, 2 equiv). Theresulting solution was stirred for 1.5 h at room temperature. The crudeproduct was purified by Prep-HPLC with the following conditions: Column:Waters HSS C18, 2.1×50 mm, 1.8 m; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% Bto 95% B in 2.0 min hold 0.6 min; Detector: UV 254 nm. The collectedfractions were lyophilized to give 37.5 mg (38% yield) of the titlecompound as a pink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.74-1.80(m, 1H), 1.81-1.90 (m, 2H), 1.92-1.95 (m, 1H), 2.63-2.67 (m, 1H),2.74-2.90 (m, 3H), 3.18-3.22 (t, J=7 Hz, 2H), 7.13-7.15 (d, J=8 Hz, 1H),7.43-7.50 (m, 2H), 7.66 (s, 1H), 8.94 (s, 1H), 11.09 (s, 1H). MS: (ES,m/z): 261 [M+H]⁺.

Example 25 Preparation of(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-122)

Step-1: Methyl(S)-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A 4-mL vial charged withmethyl-(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(10 mg, 0.040 mmol) was dissolved in 0.20 mL of anhydrous DMA. Then NaH(60% dispersion in oil, 1 mg, 0.043 mmol, 1.1 equiv) was added. Thereaction mixture was stirred for 5 min at room temperature. Next, asolution of 3-(bromomethyl)oxetane (0.20 mL, 0.040 mmol, 1 equiv) inCH₃CN was added. The reaction mixture was stirred at room temperatureovernight. The solvent was removed under a stream of N₂. The residue wasdiluted with brine (0.50 mL) and extracted with EtOAc (2×0.50 mL). Thecombined organic layers were dried under a stream of N₂ and carriedforward without further purification

Step-2:(S)-N-Hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Methyl(S)-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatewas dissolved in THF/MeOH (3:1, 200 μL). The vial was sealed and shakenat 50° C. for 15 min to dissolve the residue, then cooled to roomtemperature. NH₂OH (50% v/v in water, 0.150 mL) was added, followed by1N aq NaOH (0.10 mL, 0.10 mmol, 2.5 equiv). The mixture was sealed andthen shaken at room temperature for 18 h. The reaction mixture wasconcentrated under a stream of N₂ at room temperature, then dissolved in0.50 mL of DMSO and purified by reverse-phase chromatography Prep-HPLCColumn: Waters Sunfire C18, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1%Formic acid, Mobile Phase B: CH₃CN/0.1% Formic acid; gradient: 15% B to100% B in 6 min; Flow rate: 23 mL/min; Detector: UV 254 nm, 220 nm. Theproduct-containing fractions were combined and concentrated in to afford0.6 mg (5% yield) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.10 (s, 1H), 9.00 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.46 (d,J=7.7 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 4.80 (dd, J=7.4, 6.3 Hz, 2H),4.41 (t, J=6.2 Hz, 2H), 3.64 (d, J=7.8 Hz, 2H), 3.37-3.25 (m, 1H), 3.23(d, J=17 Hz, 1H), 3.11-3.03 (m, 1H), 2.98-2.89 (m, 1H), 2.79 (d, J=17Hz, 1H), 2.22-1.99 (m, 3H), 1.91-1.85 (m, 1H). MS: (ES, m/z) 331 [M+H]⁺.

Example 26 Preparation of(R)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-32)

Step-1: Methyl(R)-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A solution of methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(350 mg, 1.35 mmol, 1 equiv) in anhydrous DMF (6.75 mL) was deprotonatedwith NaH (60% dispersion in oil, 54 mg, 1.35 mmol, 1 equiv). Thissolution (0.15 mL, 0.30 mmol) was added to a solution of 1-iodopropane(0.2 M in acetonitrile, 0.30 mL, 0.06 mmol, 2 equiv) in a 2 dram vial.NaI (18 mg, 0.12 mmol, 4 equiv) was added and the vial was sealed andshaken at 80° C. for 48 h. The solvent was removed and the residue wasdiluted with brine (0.5 mL) and extracted with EtOAc (2×0.5 mL). Thecombined organic layers were concentrated under vacuum.

Step-2:(R)-N-Hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

The residue was dissolved in a solution of THF/MeOH (3:1, 0.2 mL). NH₂OH(50% in water, 0.15 mL, 76 equiv) was added, followed by addition of 1Naq NaOH (0.10 mL, 3.3 equiv). The mixture was sealed and shaken at roomtemperature for 18 h. The reaction mixture was concentrated and purifiedby reversed-phase chromatography Prep-HPLC Column: Waters Sunfire C18, 5μm, 19×50 mm; Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B:CH₃CN/0.1% Formic acid; Gradient: 15% B to 100% B in 6 min; Flow rate:23 mL/min; Detector: UV 254 nm, 220 nm. The product-containing fractionswere combined and concentrated to afford 3 mg (33% yield) of the titlecompound. MS: (ES, m/z) 303 [M+H]⁺.

TABLE 12 The following compounds were prepared according to the parallelsynthesis method of Example 26. Found (ES, m/z) Ex. Name Structure [M +H]⁺ I-33 (R)-1′-(cyclobutylmethyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

329 I-34 (R)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H-spirolnaphthalene-2,3′- pyrrolidine]-6-carboxamide

331 I-35 (R)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

313 I-36 (R )-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

319 I-37 (R)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

377 I-38 (R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

365 I-39 (R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]- 6-carboxamide

419 I-40 (R)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

385 I-41 (R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]- 6-carboxamide

435 I-42 (R)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo-3,4- dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

393 I-43 (R)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

388 I-44 (R)-N-hydroxy-1′-(2-methoxybenzyl)- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

381 I-45 (R)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spirofnaphthalene-2,3′- pyrrolidine]-6-carboxamide

433 I-46 (R)-N-hydroxy-1′-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

405 I-47 (R)-N-hydroxy-1′-(2-methylallyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

315 I-48 (R)-1′-(2,5-dichlorobenzyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

419 I-49 (R)-1′-(2,6-dichlorobenzyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

419 I-50 (R)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

351 I-51 (R)-N-hydroxy-1′-(3-methoxybenzyl)- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

381 I-52 (R)-N-hydroxy-2′-oxo-1′-(pyridin-2- ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

352 I-53 (R)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

369 I-54 (R)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[napthalene- 2,3′-pyrrolidine]-6-carboxamide

385 I-55 (R)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

385 I-56 (R)-N-hydroxy-1′-(4-methoxybenzyl)- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

381 I-57 (R)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

369 I-58 (R)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

401 I-59 (R)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

417  I-106 (R)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

483

TABLE 13 The following compounds were prepared according to thesynthesis method of Example 26, using methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatein Step 1. Found (ES, m/z) Ex. Name Structure [M + H]⁺ I-60(S)-N-hydroxy-2′-oxo-1′-propyl-3,4- dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

303 I-61 (S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

329 I-62 (S)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

331 I-63 (S)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

313 I-64 (S)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

319 I-65 (S)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

377 I-66 (S)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

365 I-67 (S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]- 6-carboxamide

419 I-68 (S)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

385 I-69 (S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]- 6-carboxamide

435 I-70 (S)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo-3,4- dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

393 I-71 (S)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

388 I-72 (S)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

381 I-73 (S)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

433 I-74 (S)-1′-(2,5-dichlorobenzyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

419 I-75 (S)-1′-(2,6-dichlorobenzyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

419 I-76 (S)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

351 I-77 (S)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

381 I-78 (S)-N-hydroxy-2′-oxo-1′-(pyridin-2- ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

352 I-79 (S)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

369 I-80 (S)-N-hydroxy-2′-oxo-1′-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]- 6-carboxamide

435 I-81 (S)-1′-[(3-chlorophenyl)methyl]-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-82 (S)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

385 I-83 (S)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

381 I-84 (S)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

369 I-85 (S)-1′-(4-(tert-butyl)benzyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

407 I-86 (S)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

401 I-87 (S)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

417  I-107 (S)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

483

Example 27 Preparation of(R)-N-hydroxy-1′-(naphthalen-1-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-89)

Step-1: Methyl(R)-1′-(naphthalen-1-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A 2-mL vial was charged with methyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(0.2 M in 1,4-dioxane, 0.15 mL, 0.03 mmol, 1 equiv) and Cs₂CO₃ (39 mg,0.12 mmol, 4 equiv). Then a solution of 1-bromonaphthalene (0.2 M in1,4-dioxane, 0.30 mL, 0.06 mmol, 2 equiv) was added. The vial was sealedand brought into a glovebox. A degassed solution of CuBr (10 mol %) andN,N-dimethylethane-1,2-diamine (0.02 M in DMA, 0.15 mL, 0.003 mmol, 20mol %) was added. The vial was sealed and heated at 110° C. for 18 h.The solvent was removed and the residue was diluted with brine (0.5 mL)and extracted with EtOAc (2×0.5 mL). The combined organic layers wereconcentrated under vacuum.

Step-2:(R)-N-Hydroxy-1′-(naphthalen-1-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

The residue was dissolved in THF/MeOH (3:1, 0.2 mL) and NH₂OH (50% inwater, 0.15 mL, 76 equiv) was added, followed by addition of 1N aq NaOH(0.1 mL, 3.3 equiv). The mixture was sealed and then shaken at roomtemperature for 18 h. The reaction mixture was concentrated and purifiedby reverse-phase Prep-HPLC Column: Waters Sunfire C18, 5 μm, 19×50 mm;Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH₃CN/0.1%Formic acid; Gradient: 15% B to 100% B in 6 min; Flow rate: 23 mL/min;Detector: UV 254 nm/220 nm. The product-containing fractions werecombined and concentrated to afford 1 mg (8.6% yield) of the titlecompound. MS: (ES, m/z) 387 [M+H]⁺.

TABLE 14 The following compounds were prepared according to the parallelsynthesis method of Example 27. Found (ES, m/z) Ex. Name Structure [M +H]⁺ I-90  (R)-1′-(3-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-91  (R)-1′-(benzo[d][1,3]dioxol-5-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

381 I-92  (R)-N-hydroxy-1′-(3- (methylthio)phenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- pyrrolidine]-6-carboxamide

383 I-93  (R)-1′-(4-(dimethylamino)phenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

380 I-94  (R)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

380 I-95  (R)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

388 I-96  (R)-1′-(2,3-dihydrobenzofuran-7-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

379 I-97  (R)-1′-(6-(tert-butylamino)pyrimidin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

410 I-98  (R)-1′-(1,3-dimethyl-1H-pyrazol-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

355 I-99  (R)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

377 I-108 (R)-N-hydroxy-1′-(3-methoxyphenyl)- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3-pyrrolidine]-6- carboxamide

367 I-110 (R)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

356 I-124 (R)-N-hydroxy-1′-(4-methoxyphenyl)- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

367 I-131 (R)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-133 (R)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-135 (R)-N-hydroxy-1′-(5-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-136 (R)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-139 (R)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

372 I-140 (R)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

372 I-143 (R)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-145 (R)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-149 (R)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-168 (R)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

341 I-114 (R)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-111 (R)-N-hydroxy-1′-(2-methoxyphenyl)- 2′-oxo-3,4-dihydro-1H-spiro]naphthalene-2,3′-pyrrolidine]-6- carboxamide

367 I-125 (2R)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-128 (2R)--(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-151 (2R)-1′-[6-(dimethylamino)pyridin-3-yl]-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

381

TABLE 15 The following compounds were prepared according to the parallelsynthesis method of Example 27, using methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatein Step 1. Found (ES, m/z) Ex. Name Structure [M + H]⁺ I-100(S)-1′-(2,4-dimethylphenyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

365 I-101 (S)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

380 I-102 (S)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

388 I-103 (S)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4-dihydro-1H-spiro]naphthalene-2,3′-pyrrolidine]-6- carboxamide

377 I-130 (S)-1′-(5-chloropyridin-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

372 I-132 (S)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-134 (S)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-138 (S)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

372 I-141 (S)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

372 I-142 (S)-N-hydroxy-1′-(4-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-146 (S)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-150 (S)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-170 (S)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3-pyrrolidine]-6- carboxamide

341 I-118 (S)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-115 (S)-N-hydroxy-1′-(2-methoxyphenyl )- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

367 I-126 (2S)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-127 (2S)-1′-(2-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-129 (2S)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-137 (S)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

352 I-144 (2S)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

368 I-147 (2S)-1′-(2-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-148 (2S)-1′-(3-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

385 I-152 (2S)-1′-[6-(dimethylamino)pyridin-3-yl]-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

381 I-153 (2S)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

356

Example 28 Preparation of(R)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-119)

Step-1: Methyl(R)-1′-(3,4-difluorophenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A 2-dram vial was charged with (Xantphos)PdCl₂ (0.02 M, 0.150 mL, 0.30μmol) in CH₂Cl₂. The solvent was then evaporated under a stream of N₂.Next 4-bromo-1,2-difluorobenzene in 1,4-dioxane (0.2 M, 0.200 mL, 0.030mmol) was added followed by Cs₂CO₃ (39 mg, 0.120 mmol). The vial wascapped and carried into an inert atmosphere glovebox where a solution ofmethyl(R)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatein dioxane/Et₃N (98:2, 0.20 M, 0.200 mL, 0.030 mmol) was added. The vialwas capped and heated at 100° C. for 16 h. The solvent was removed undera stream of N₂. The residue was diluted with brine (0.50 mL) andextracted with EtOAc (2×0.50 mL). The combined organic layers were driedunder a stream of N₂.

Step-2:(R)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

The residue was dissolved in THF/MeOH (3:1, 0.20 mL). The vial wassealed and shaken at 50° C. for 15 min to dissolve the residue, thencooled to room temperature. NH₂OH (50% v/v solution in water, 0.150 mL)was added, followed by 1N aq NaOH (0.10 mL). The mixture was sealed andthen shaken at room temperature for 18 h. The reaction mixture wasconcentrated under a stream of N₂ at room temperature, then dissolved in0.50 mL of DMSO and purified by reverse-phase chromatography HPLCColumn: Waters Sunfire C18, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1%Formic acid, Mobile Phase B: CH₃CN/0.1% Formic acid; Gradient: 15% B to100% B in 6 min; Flow rate: 23 mL/min; Detector: UV 254 nm, 220 nm. Theproduct-containing fractions were combined and concentrated in a Genevacto afford 3.3 mg (28% yield) of the title compound. ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.70 (br s, 1H), 7.77 (ddd, J=12, 7.0, 2.7 Hz, 1H), 7.56(s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.33-7.29 (m, 1H), 7.20 (d, J=10 Hz,1H), 7.15 (d, J=10 Hz, 1H), 3.82 (t, J=6.6 Hz, 2H), 3.15 (d, J=17 Hz,1H), 3.06-2.99 (m, 1H), 2.94-2.85 (m, 1H), 2.75 (d, J=17 Hz, 1H),2.18-1.94 (m, 3H), 1.88-1.82 (m, 1H). MS: (ES, m z) 373 [M+H]⁺.

TABLE-16 The following compounds were prepared according to the parallelsynthesis method of Example 28. Found (ES, m/z) Ex. Name Structure [M +H]⁺ I-167 (R)-1′-(2,5-difluorophenyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3'-pyrrolidine]-6- carboxamide

373 I-120 (R)-1′-(4-fluorophenyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

355 I-113 (R)-1′-(3-fluorophenyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

355 I-121 (R)-1′-(2-fluorophenyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

355 I-123 (R)-1′-(2,3-difluorophenyl)-N-hydroxy- 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide

373

TABLE-17 The following compounds were prepared according to thesynthesis method of Example 28, using methyl(S)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate in Step 1. Found (ES, m/z) Ex. Name Structure [M + H]⁺ I-154(S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

355 I-156 (S)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

373 I-155 (S)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

373 I-157 (S)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

355 I-158 (S)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

367 I-169 (S)-1′-(2,5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

373 I-117 (S)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene- 2,3′-pyrrolidine]-6-carboxamide

355

Example 29 Preparation ofN-hydroxy-2-oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-242)

Step-1: 6-Bromo-4-oxothiochromane-2-carboxylic acid

In a 100-mL 3-necked round-bottom flask 4-bromobenzenethiol (20.0 g,105.78 mmol, 1 equiv) in toluene (25 mL) and 2,5-dihydrofuran-2,5-dione(12.96 g, 132.17 mmol, 1 equiv) were stirred at 50° C. for 1 h. Asolution of Et₃N (27.6 mg, 0.28 mmol) in toluene (0.4 mL) was thenadded, ensuring the reaction temperature did not increase over 60° C.The reaction was heated at 70° C. for 50 min. The reaction was thenconcentrated under high vacuum. The residue was dissolved in CH₂Cl₂ (109mL), cooled to 0° C. in an ice bath and treated with AlCl₃ (14.52 g,108.89 mmol, 1.03 equiv). The reaction was slowly warmed to roomtemperature. After stirring for 3 h the reaction mixture was thendiluted with CH₂Cl₂ (18 mL) and slowly poured into vigorously stirredconcentrated HCl (44 mL) and ice (44 g). The reaction was vigorouslystirred and diluted with CH₂Cl₂ (500 mL) and isopropanol (72 mL). TheCH₂Cl₂ layer was separated, dried over magnesium sulfate, filtered andconcentrated in vacuum. The mixture was triturated with Et₂O and thenfiltered to give 6.64 g (22% yield) of the title compound as a lightyellow solid. MS: (ES, m/z): 285 [M+H]⁺.

Step-2: 6-Bromothiochromane-2-carboxylic acid

Into a 500-mL round-bottom flask was placed a solution of6-bromo-4-oxothiochromane-2-carboxylic acid (4.0 g, 13.93 mmol, 1 equiv)in TFA (200 mL). This was followed by the addition of triethylsilane (16g, 137.60 mmol, 10 equiv) at 0° C. The resulting solution was stirredfor 19 h at room temperature. The resulting mixture was concentratedunder vacuum. The residue was dissolved in 100 mL of CH₂Cl₂ and washedwith 2×40 mL of H₂O, dried over anhydrous magnesium sulfate, filtered,and concentrated under vacuum. The residue was dissolved in 30 mL ofH₂O. The pH of the solution was adjusted to 9 with aq. NaOH. Theresulting solution was washed with 2×50 mL of CH₂Cl₂ and the aqueouslayers combined. 6N aq. HCl was employed to adjust the pH to 4. Theresulting solution was extracted with 3×70 mL of CH₂Cl₂. The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and then concentrated under vacuum to give 1.42 g (37% yield) of thetitle compound as a light yellow solid. MS: (ES, m/z): 271 [M+H]⁺.

Step-3: Methyl 6-bromothiochromane-2-carboxylate

Into a 50-mL round-bottom flask was placed a solution of6-bromothiochromane-2-carboxylic acid (1.42 g, 5.20 mmol, 1 equiv) inMeOH (15 mL) and concentrated sulfuric acid (2.84 mL). The resultingsolution was stirred for 15 h at 70° C. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in 100 mL ofCH₂Cl₂. The resulting mixture was washed with 2×50 mL of H₂O, washedwith 3×50 mL of NaHCO₃ and 2×50 mL of brine. The organic layer was driedover anhydrous magnesium sulfate, filtered, and concentrated undervacuum to give 1.28 g (86% yield) of the title compound as a yellowsolid. MS: (ES, m/z): 285 [M+H]⁺.

Step-4: Dimethyl thiochromane-2,6-dicarboxylate

Into a 50-mL pressure tank reactor (30 atm), was placed a solution ofmethyl 6-bromothiochromane-2-carboxylate (1.28 g, 4.47 mmol, 1 equiv) inMeOH (15 mL), Et₃N (1.85 mL), and Pd(dppf)Cl₂ (655 mg, 0.90 mmol, 0.20equiv). CO (g) was introduced into the reactor. The resulting solutionwas stirred for 2 days at 100° C. The resulting mixture was concentratedunder vacuum. The residue was purified by normal phase chromatography onsilica gel with EtOAc/petroleum ether (1:3). The collected fractionswere concentrated to give 811 mg (68% yield) of the title compound as alight brown solid. MS: (ES, m/z): 267 [M+H]⁺.

Step-5: Dimethyl 2-(cyanomethyl)thiochromane-2,6-dicarboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of dimethylthiochromane-2,6-dicarboxylate (1.55 g, 5.83 mmol, 1 equiv) in THF (20mL). This was followed by the addition of LDA (7 mL, 1.2 equiv) at −78°C. over 30 min. To this was added 2-bromoacetonitrile (910.6 mg, 7.59mmol, 1.3 equiv) at −78° C. The resulting solution was stirred for 1.5 hat the same temperature. The reaction was then quenched by the additionof 35 mL of sat. aq. NH₄Cl. The resulting solution was extracted with2×100 mL of EtOAc. The organic layers were combined and concentratedunder vacuum. The residue was purified by normal phase chromatography onsilica gel with EtOAc/petroleum ether (1:3). The collected fractionswere concentrated to give 1.51 g (85% yield) of the title compound as ayellow oil. MS: (ES, m/z): 304 [M−H]⁻.

Step-6: Dimethyl 2-(cyanomethyl)thiochromane-2,6-dicarboxylate1,1-dioxide

Into a 250-mL round-bottom flask was placed a solution of dimethyl2-(cyanomethyl)thiochromane-2,6-dicarboxylate (1.51 g, 4.95 mmol, 1equiv) in CH₂Cl₂ (150 mL). This was followed by the addition of asolution of m-CPBA (2.57 g, 14.87 mmol, 3 equiv) in CH₂Cl₂ (10 mL) at 0°C. The resulting mixture was stirred for 14 h at room temperature. ThenK₂CO₃ (1 g) was added and the reaction stirred for 1 h at roomtemperature. The solids were filtered out. The solid was washed with 100mL of CH₂Cl₂. The filtrate was concentrated under vacuum to give 1.79 g(crude) of the title compound as a yellow oil. MS: (ES, m/z): 336[M−H]⁻.

Step-7: Methyl 2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide

Into a 500-mL round-bottom flask was placed a solution of dimethyl2-(cyanomethyl)thiochromane-2,6-dicarboxylate 1,1-dioxide (1.79 g, 5.31mmol, 1 equiv) in MeOH (150 mL), PtO₂ (675 mg, 2.97 mmol, 0.6 equiv),and acetic acid (33.4 mL). Hydrogen (g) was introduced. The resultingsolution was stirred for 1 day at room temperature. The solids werefiltered out and the filtrate was concentrated under vacuum. The pH ofthe solution was adjusted to 9 with aq. Na₂CO₃. The resulting solutionwas extracted with 3×100 mL of CH₂Cl₂, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum to give 1.27 g (78%yield) of the title compound as a gray solid. ¹H-NMR (400 MHz, DMSO-d6)δ (ppm): 8.06-8.01 (m, 3H), 6.00 (s, 1H), 3.97 (s, 3H), 3.71-3.55 (m,2H), 3.49-3.43 (m, 1H), 3.16-3.05 (m, 2H), 2.71-2.63 (m, 2H), 2.31-2.23(m, 1H). MS: (ES, m/z): 310 [M+H]⁺.

Step-8:2-Oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylicacid 1′,1′-dioxide

Into an 8-mL vial, was placed a solution of methyl2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate 1′,1′-dioxide(100 mg, 0.32 mmol, 1 equiv) in DMF (3 mL). This was followed by theaddition of NaH (60% dispersion in oil, 65 mg, 2.71 mmol, 5 equiv) at 0°C. over 10 min. To this was added 4-(bromomethyl) pyridine hydrobromide(163 mg, 0.64 mmol, 2 equiv). The resulting mixture was stirred for 18 hat room temperature. The reaction was then quenched by the addition ofNH₄Cl (aq.). The resulting solution was extracted with 2×20 mL of EtOAcand the aqueous layers combined. The pH of the aqueous layers wasadjusted to 4 with 1N aq. HCl. The resulting solution was extracted with3×20 mL of CH₂Cl₂, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum to give 30 mg (24% yield) of the titlecompound as a light brown oil which was used in the next step withoutpurification. MS: (ES, m/z): 387 [M+H]⁺.

Step-9:N-Hydroxy-2-oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide

Into an 8-mL vial, was placed a solution of2-oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylicacid 1′,1′-dioxide (55 mg, 0.14 mmol, 1 equiv) in DMA (1.5 mL). This wasfollowed by the dropwise addition of isopropyl chloroformate (90 mg,0.71 mmol, 5 equiv) with stirring at 0° C. over 15 min. NMM (72 mg, 0.71mmol, 5 equiv) was added dropwise with stirring at 0° C. The mixture wasstirred for 15 min at 0° C. A solution of NH₂OH.HCl (50 mg, 0.71 mmol, 5equiv) in DMA (0.5 mL) was added to the stirring mixture. The resultingsolution was stirred for 19 h at room temperature. The crude product waspurified by Prep-HPLC with the following conditions: Column: SunfirePrep C18, 5 μm, 19×100 mm; Mobile Phase A: Water/0.05% TFA, Mobile PhaseB: CH₃CN/0.05% TFA; Flow rate: 25 ml/min; Gradient: 4% B to 58% B in 7min; Detector: UV 254 nm, 220 nm. The collected fractions werelyophilized to give 8 mg (11% yield) of the title compound as a brownsolid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.41 (br s, 1H), 8.66 (s,2H), 7.90-7.88 (m, 1H), 7.80-7.74 (m, 2H), 7.48 (s, 2H), 4.74-4.70 (m,1H), 4.52-4.44 (m, 1H), 3.42-3.33 (m, 2H), 3.16-3.04 (m, 2H), 2.75-2.67(m, 3H), 2.37-2.29 (m, 1H). MS: (ES, m z): 402 [M+H]⁺.

TABLE-18 The following compound was prepared according to the method ofExample 29. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-239

(400 MHz, DMSO-d6): 11.41 (br s, 1H), 7.89-7.87 (d, J = 8.0 Hz, 1H),7.79-7.74 (m, 2H), 7.37-7.24 (m, 5H), 4.58-4.55 (d, J = 12.0 Hz, 1H),4.35- 4.31 (d, J = 16.0 Hz, 1H), 3.41-3.29 (m, 3H), 3.10-3.02 (m, 1H),2.70-2.61 (m, 2H), 2.48-2.43 (m, 1H), 2.28-2.21 (m, 1H) 401

Example 30 Preparation ofN-hydroxy-2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-238)

Step-1: Methyl2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide

Into a 25-mL vial purged and maintained with an inert atmosphere ofnitrogen, were placed methyl2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate 1′,1′-dioxide(100 mg, 0.32 mmol, 1 equiv), Cs₂CO₃ (211 mg, 0.65 mmol, 2 equiv) in1,4-dioxane (6 mL), XantPhos (41 mg, 0.07 mmol, 0.22 equiv), iodobenzene(79 mg, 0.39 mmol, 1.2 equiv), and Pd(OAc)₂ (7.3 mg, 0.03 mmol, 0.1equiv). The resulting mixture was stirred for 17 h at 100° C. and thenconcentrated under vacuum. The residue was dissolved in 30 mL of EtOAcand washed with 3×20 mL of H₂O. The organics were dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby normal phase chromatography on silica gel with EtOAc/petroleum ether(5:6). The collected fractions were concentrated to give 60.5 mg (49%yield) of the title compound as a light brown oil. MS: (ES, m/z): 386[M+H]⁺.

Step-2:N-Hydroxy-2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide

Into an 8-mL vial, was placed a solution of methyl2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide (60.5 mg, 0.16 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL),NH₂OH (50% in H₂O, 0.31 mL, 30 equiv) and 1N aq. NaOH (0.31 mL, 2equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge C18, 5 μm, 19×100 mm; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 25 mL/min;Gradient: 5% B to 57% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to give 45.9 mg (76% yield) of thetitle compound as a pink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.42(br s, 1H), 7.90-7.87 (d, J=12.0 Hz, 1H), 7.80-7.76 (m, 2H), 7.66-7.64(d, J=8.0 Hz, 2H), 7.43-7.38 (m, 2H), 7.26-7.18 (m, 1H), 4.09-3.89 (m,2H), 3.40-3.30 (m, 1H), 3.19-3.05 (m, 1H), 2.84-2.75 (m, 2H), 2.57-2.55(m, 1H), 2.44-2.39 (m, 1H). MS: (ES, m/z): 387 [M+H]⁺.

TABLE-19 The following compound was prepared according to the method ofExample 30. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-240

(400 MHz, DMSO-d6): 11.43 (br s, 1H), 8.95-8.94 (d, J = 4.0 Hz, 1H),8.46-8.45 (d, J = 4 Hz, 1H), 8.20-8.17 (d, J = 12 Hz, 1H), 7.91-7.88(d,J = 12 Hz, 1H), 7.81-7.77 (m, 2H), 7.57-7.52 (m, 1H), 4.06-4.01 (m, 2H),3.40-3.29 (m, 1H), 3.16-3.06 (m, 1H), 2.89-2.77 (m 2H), 2.59-2.56 (m,1H), 2.46-2.39 (m, 1H) 388

Example 31 Preparation ofN-hydroxy-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-241)

Step-1: Methyl2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide

Into a 25-mL vial, was placed a solution of methyl2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate 1′,1′-dioxide(150 mg, 0.48 mmol, 1 equiv) in DMF (4 mL). This was followed by theaddition of NaH (60% dispersion in oil, 39 mg, 1.62 mmol, 2 equiv) at 0°C. over 10 min. 4-(Bromomethyl)oxane (261 mg, 1.46 mmol, 3 equiv) wasthen added. The resulting solution was stirred for 4 h at roomtemperature. The reaction was quenched with a solution of aq. NH₄Cl. Theresulting solution was extracted with 3×20 mL of EtOAc. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give 144.8 mg (73% yield) of the titlecompound as a light yellow oil. MS: (ES, m/z): 408 [M+H]⁺.

Step-2:N-Hydroxy-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide

Into an 8-mL vial, was placed a solution of methyl2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide (100 mg, 0.25 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL),NH₂OH (50% in H₂O, 0.48 mL, 30 equiv), and aq. NaOH (1N, 0.49 mL, 2equiv). The resulting solution was stirred for 5 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge C18, 19×150 mm, 5 μm; Mobile Phase A:Water/0.05% TFA, CH₃CN/0.05% TFA; Flow rate: 25 mL/min; Gradient: 5% Bto 57% B in 6 min; Detector: UV 254 nm, 220 nm. The collected fractionswere lyophilized to give 15 mg (15% yield) of the title compound as apink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.40 (br s, 1H),7.85-7.83 (d, J=8.0 Hz, 1H), 7.77-7.71 (m, 2H), 3.83-3.80 (m, 2H),3.50-3.44 (m, 3H), 3.35-3.24 (m, 3H), 3.05-2.98 (m, 2H), 2.67-2.63 (m,2H), 2.42-2.40 (m, 1H), 2.24-2.22 (m, 1H), 1.89-1.79 (m, 1H), 1.56-1.48(m, 2H), 1.14-1.05 (m, 2H). MS: (ES, m/z): 409 [M+H]⁺.

Example 32 Preparation ofN-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-243)

Into an 8-mL vial, was placed a solution of methyl2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate 1′,1′-dioxide(50 mg, 0.16 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), NH₂OH (50% in H₂O,0.48 mL, 30 equiv), and 1N aq. NaOH (0.32 mL, 2 equiv). The resultingsolution was stirred for 2 h at room temperature. The crude product waspurified by Prep-HPLC with the following conditions: Column: XbridgeC18, 19×150 mm, 5 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B:CH₃CN/0.05% TFA; Flow rate: 25 mL/min; Gradient: 5% B to 57% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized togive 4.6 mg (9% yield) of the title compound as a brown oil. ¹H-NMR (400MHz, DMSO-d6) δ (ppm): 11.39 (br s, 1H), 9.21 (br s, 1H), 8.35 (s, 1H),7.86-7.84 (d, J=8.0 Hz, 1H), 7.77-7.75 (d, J=8.0 Hz, 1H), 7.70 (s, 1H),3.33-3.27 (m, 3H), 3.05-2.98 (m, 1H), 2.71-2.60 (m, 2H), 2.43-2.32 (m,1H), 2.27-2.20 (m, 1H). MS: (ES, m/z): 311 [M+H]⁺.

Example 33 Preparation ofN-hydroxy-1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-244)

Step-1: Methyl1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide

Into an 8-mL vial, was placed a solution of methyl2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate 1′,1′-dioxide(80 mg, 0.26 mmol, 1 equiv) in DMF (3 mL) and Cs₂CO₃ (104 mg, 0.75 mmol,3 equiv). This was followed by the dropwise addition of CH₃I (74 mg,0.52 mmol, 2 equiv) with stirring at 0° C. The resulting mixture wasstirred for 14 h at room temperature. The reaction was diluted with 20mL of water and extracted with 2×20 mL of CH₂Cl₂. The organic layerswere combined and washed with 3×10 mL of H₂O, dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby normal phase chromatography on silica gel with CH₂Cl₂/MeOH (25:1) togive 46.4 mg (55% yield) of the title compound as a light yellow oil.MS: (ES, m/z): 324 [M+H]⁺.

Step-2:N-Hydroxy-1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide

Into an 8-mL vial, was placed a solution of methyl1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxylate1′,1′-dioxide (46.4 mg, 0.14 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL),NH₂OH (50% in H₂O, 0.28 mL, 30 equiv), and 1N aq. NaOH (0.29 mL, 2equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge C18, 19×150 mm, 5 μm; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05% TFA; Flow rate: 25 mL/min;Gradient: 4% B to 56% B in 7 min; Detector: UV 254 nm, 220 nm. Thecollected fractions were lyophilized to give 14.4 mg (23% yield) of thetitle compound as a brown oil. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.40(br s, 1H), 9.21 (br s, 1H), 7.85-7.71 (m, 3H), 3.45-3.41 (m, 3H),3.05-2.98 (m, 1H), 2.78 (s, 3H), 2.66-2.59 (m, 2H), 2.49-2.41 (m, 1H),2.20-2.19 (m, 1H). MS: (ES, m/z): 325 [M+H]⁺.

Example 34 Preparation of(R)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-201)

Step-1: 6-Bromo-3,4-dihydronaphthalene-2-carbonitrile

Into a 500-mL round-bottom flask, was placed a solution of6-bromo-3,4-dihydronaphthalen-2(1H)-one (15.00 g, 66.64 mmol, 1 equiv)in toluene (150 mL), TMSCN (7.29 g, 1 equiv), and ZnI₂ (513 mg, 0.02equiv). The resulting solution was stirred overnight at 25° C. Thenpyrazine (100 mL) and POCl₃ (30 mL) were added to the solution andallowed to react with stirring for 4 h at 110° C. The reaction was thenquenched by the addition of 1000 mL of 10% HCl aqueous solution at 0° C.The resulting solution was extracted with 3×500 mL of EtOAc. Thecombined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by normal phasecolumn chromatography on silica gel with EtOAc/petroleum ether (1:10).The collected fractions were concentrated under vacuum to give 6 g (38%yield) of the title compound as a yellow solid. MS: (ES, m/z): 234[M+H]⁺.

Step-2: Methyl 6-cyano-7,8-dihydronaphthalene-2-carboxylate

Into a 100-mL pressure tank reactor (60 atm), was placed a solution of6-bromo-3,4-dihydronaphthalene-2-carbonitrile (6.00 g, 25.63 mmol, 1equiv) in MeOH (40 mL), Pd(dppf)Cl₂ (1.88 g, 2.57 mmol, 0.10 equiv) andEt₃N (7.80 g, 77.08 mmol, 3 equiv). CO (g) was introduced to the flask.The resulting solution was stirred overnight at 130° C. The resultingmixture was concentrated under vacuum. The residue was purified bynormal phase column chromatography on silica gel with EtOAc/petroleumether (1:3). The collected fractions were concentrated under vacuum togive 4.0 g (73% yield) of the title compound as a yellow solid. MS: (ES,m/z): 214 [M+H]⁺.

Step-3: Methyl 6-cyano-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Into a 500-mL round-bottom flask, was placed a solution of methyl6-cyano-7,8-dihydronaphthalene-2-carboxylate (3.00 g, 14.07 mmol, 1equiv) in MeOH (200 mL). Then magnesium (3.38 g, 139.07 mmol, 10 equiv)was added at 0° C. The resulting solution was stirred for 30 min at 0°C. The resulting mixture was the poured into 100 mL of water and MeOHwas evaporated under vacuum. The pH of the solution was adjusted to 3with 2N HCl at 0° C. The resulting solution was extracted with 3×100 mLof CH₂Cl₂, dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by normal phase column chromatographyon silica gel with EtOAc/petroleum ether (1:10). The collected fractionswere concentrated under vacuum to give 1.9 g (63% yield) of the titlecompound as a white solid. MS: (ES, m/z): 216 [M+H]⁺.

Step-4: Methyl6-cyano-6-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl6-cyano-5,6,7,8-tetrahydronaphthalene-2-carboxylate (1.50 g, 6.97 mmol,1 equiv) in THF (90 mL). LDA (2M in THF, 13.95 mL, 2 equiv) was addeddropwise into the solution at −78° C. The resulting solution was stirredfor 1 h at −78° C. 2-Bromoacetate (2.12 g, 1 equiv) was the addeddropwise into the solution at −78° C. The resulting solution was allowedto react with stirring for 3 h at 25° C. The reaction was then quenchedby the addition of 150 mL of aq. NH₄Cl solution, then extracted with3×100 mL of EtOAc. The combined organics were dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby normal phase column chromatography on silica gel with EtOAc/petroleumether (1:5). The collected fractions were concentrated under vacuum togive 450 mg (22% yield) of the title compound as a yellow solid. MS:(ES, m/z): 288 [M+H]⁺.

Step-5: Methyl5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of methyl6-cyano-6-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate(550 mg, 1.91 mmol, 1 equiv) in MeOH (25 mL), PtO₂ (225 mg, 0.99 mmol),and AcOH (5 mL, 87.26 mmol). Hydrogen gas was introduced into the flaskand the resulting solution was stirred for 1 h at 25° C. The solids werefiltered out and the filtrate was concentrated under vacuum. The residuewas dissolved in 7M NH₃ in MeOH (25 mL) and allowed to react withstirring for 1 h at 25° C. The resulting mixture was concentrated undervacuum and the residue was purified by normal phase columnchromatography on silica gel with CH₂Cl₂/MeOH (100:1). The collectedfractions were concentrated under vacuum to give 250 mg (50% yield) ofthe title compound as a white solid. MS: (ES, m/z): 260 [M+H]⁺.

Step-6: Chiral separation of methyl(R)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateand methyl(S)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

250 mg of the racemate methyl5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylatewas separated by Chiral-Prep-HPLC with the following conditions: Column:Phenomenex Lux 5u Cellulose-4AXIA Packed, 250×21.2 mm, 5 μm; MobilePhase A: Hexanes, Mobile Phase B: EtOH; Gradient: hold 30% B in 25 min;Detector: UV 254 nm, 220 nm. The first eluting isomer (Rt 3.626 min) wascollected and concentrated under vacuum to give 105 mg (42% yield) of awhite solid which was assigned as the R isomer of methyl5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate.MS: (ES, m/z): 260 [M+H]⁺. The second eluting isomer (Rt 4.410 min) wascollected and concentrated under vacuum to give 100 mg (40% yield) of awhite solid which was assigned as the S isomer of methyl5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas a white solid. MS: (ES, m/z): 260 [M+H]⁺.

Step-7: Methyl(R)-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 10-mL round-bottom flask, was placed a solution of the firsteluted isomer from Step 6, which was assigned as methyl(R)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). NaH (60%dispersion in oil, 9 mg, 2 equiv) was added into the solution at 0° C.The resulting mixture was stirred for 1 h at 25° C. Iodomethane (55 mg,0.39 mmol, 2 equiv) was added into the solution and the resultingsolution was allowed to react with stirring for 1 h at 25° C. Thereaction was then quenched by the addition of 15 mL of water, extractedwith 3×15 mL of EtOAc. The combined extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum to give 50 mg (90% yield)of the title compound as a yellow solid. MS: (ES, m/z): 274 [M+H]⁺.

Step-8:(R)-N-Hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 10-mL round-bottom flask, was placed a solution of the productfrom Step 7, which was assigned as methyl(R)-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (50 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL),NH₂OH (50% in water, 725 mg, 14.20 mmol, 120 equiv), and 1N aq. NaOH(14.4 mg, 0.36 mmol, 2 equiv). The resulting solution was stirred for 2h at 25° C. The crude product was purified by Prep-HPLC with thefollowing conditions: Column: XBridge Prep C18 OBD, 19×150 mm 5 μm;Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH₃CN; Gradient:5% B to 30% B in 7 min; Detector: UV 254 nm, 220 nm. The collectedfractions were lyophilized to give 17.9 mg (36% yield) of the titlecompound as a light pink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.08(s, 1H), 8.95 (s, 1H), 7.51 (s, 1H), 7.47-7.45 (d, J=8.0 Hz, 1H),7.13-7.11 (d, J=8.0 Hz, 1H), 3.24-3.22 (d, J=9.6 Hz, 1H), 3.08-3.05 (d,J=9.6 Hz, 1H), 2.86-2.82 (m, 2H), 2.78-2.76 (d, J=8.4 Hz, 2H), 2.71 (s,3H), 2.27-2.23 (d, J=16.4 Hz, 1H), 2.03-1.99 (d, J=16.4 Hz, 1H),1.80-1.76 (m, 2H). MS: (ES, m/z): 275 [M+H]⁺.

TABLE-20 The following compounds were prepared according to the methodof Example 34, with the following modifications: (1) In Step 7, thefirst eluted product from Step 6 was used; (2) in Step 7, the halide canbe an iodide, a chloride, or a bromide. Found (ES, m/z) Ex. Structure¹H-NMR δ (ppm) [M + H]⁺ I-215

(300 MHz, DMSO-d6): 7.51 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.13 (d, J =8.1 Hz, 1H), 4.64-4.59 (m, 2H), 4.31- 4.26 (m, 2H), 3.49 (d, J = 7.5 Hz,2H), 3.21-3.11 (m, 2H), 3.05 (d, J = 9.6 Hz, 1H), 2.86-2.82 (m, 2H),2.75 (s, 2H), 2.27 (d, J = 16.5 Hz, 1H), 2.04 (d, J = 16.5 Hz, 1H),1.79-1.75 (m, 2H) 331 I-219

(300 MHz, DMSO-d6 + D₂O): 7.51 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.13(d, J = 8.1 Hz, 1H), 3.29-3.18 (m, 8H), 3.08 (d, J = 9.6 Hz, 1H),2.87-2.83 (m, 2H), 2.77-2.76 (m, 2H), 2.27 (d, J = 16.2 Hz, 1H), 2.04(d, J = 16.5 Hz, 1H), 1.81- 1.77 (m, 2H), 1.70-1.61 (m, 2H) 333 I-206

(300 MHz, DMSO-d6): 10.95 (s, 1H), 8.95 (s, 1H), 7.52 (s, 1H), 7.48 (d,J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 3.32-3.17 (m, 3H), 3.08 (d, J= 9.9 Hz, 1H), 2.87-2.76 (m, 4H), 2.26 (d, J = 16.2 Hz, 1H), 2.03 (d, J= 16.5 Hz, 1H), 1.81-1.79 (m, 2H), 1.03-1.00 (m, 3H) 289 I-220

(300 MHz, DMSO-d6): 10.80 (s, 1H), 9.00 (s, 1H), 7.52 (s, 1H), 7.48 (d,J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 4.11-4.02 (m, 2H), 3.38-3.35(m, 1H), 3.25-3.22 (m, 1H), 2.87-2.83 (m, 2H), 2.80-1.73 (m, 2H), 2.37(d, J = 16.8 Hz, 1H), 2.15 (d, J = 16.8 Hz, 1H), 1.81- 1.79 (m, 2H) 343I-207

(400 MHz, DMSO-d6): 11.11 (s, 1H), 8.98 (s, 1H), 7.53-7.47 (m, 2H), 7.14(d, J = 8.0 Hz, 1H), 3.24 (d, J = 9.6 Hz, 1H), 3.09 (d, J = 9.6 Hz, 1H),2.99 (d, J = 7.6 Hz, 2H), 2.88-2.78 (m, 4H), 2.30 (d, J = 16.4 Hz, 1H),2.07 (d, J = 16.4 Hz, 1H), 1.85-1.79 (m, 3H), 0.85-0.83 (m, 6H) 317I-208

(400 MHz, DMSO-d6): 11.11 (s, 1H), 8.96 (s, 1H), 7.52-7.46 (m, 2H), 7.13(d, J = 8.0 Hz, 1H), 4.19-4.15 (m, 1H), 3.15 (d, J = 10.0 Hz, 1H), 3.03(d, J = 9.6 Hz, 1H), 2.87-2.74 (m, 4H), 2.25 (d, J = 16.4 Hz, 1H), 2.03(d, J = 16.4 Hz, 1H), 1.80-1.76 (m, 2H), 1.05-1.02 (m, 6H) 303 I-216

(400 MHz, DMSO-d6): 11.05 (s, 1H), 8.96 (s, 1H), 7.47 (s, 1H), 7.44 (d,J = 8.0 Hz, 1H), 7.38-7.21 (m, 5H), 7.06 (d, J = 8.0 Hz, 1H), 7.37 (s,2H), 3.11 (d, J = 9.6 Hz, 1H), 2.96 (d, J = 9.6 Hz, 1H), 2.87-2.71 (m,4H), 2.35 (d, J = 16.8 Hz, 1H), 2.13 (d, J = 16.8 Hz, 1H), 1.75 (s, 2H)351 I-225

(400 MHz, DMSO-d6): 11.04 (br s, 1H), 8.96 (br s, 1H), 7.48-7.43 (m,2H), 7.18-7.14 (m, 4H), 7.09 (d, J = 8 Hz, 1H), 4.39 (s, 2H), 3.05 (d, J= 10 Hz, 1H), 2.92 (d, J = 9.6 Hz, 1H), 2.87-2.71 (m, 4H), 2.37 (d, J =16.4 Hz, 1H), 2.24 (s, 3H), 2.14 (d, J = 16.4 Hz, 1H), 1.79- 1.74 (m,2H) 365

TABLE-21 The following compounds were prepared according to the methodof Example 34, with the following modifications: (1) In Step 7, thesecond eluted product from Step 6 was used; (2) In Step 7, the halidecan be an iodide, a chloride, or a bromide. Found (ES, m/z) Ex.Structure ¹H-NMR δ (ppm) [M + H]⁺ I-202

(300 MHz, DMSO-d6): 11.01 (s, 1H), 8.94 (s, 1H), 7.51 (s, 1H), 7.47 (d,J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 3.23 (d, J = 9.9 Hz, 1H),3.07 (d, J = 9.9 Hz, 1H), 2.84 (m, 2H), 2.77-2.76 (m, 2H), 2.71 (s, 3H),2.25 (d, J = 16.5 Hz, 1H), 2.02 (d, J = 16.5 Hz, 1H), 1.80-1.76 (m, 2H)275 I-210

(300 MHz, DMSO-d6): 11.08 (br s, 1H), 8.95 (br s, 1H), 7.51-7.45 (m,2H), 7.12 (d, J = 8.1 Hz, 1H), 3.21-3.17 (m, 3H), 3.04 (d, J = 9.9 Hz,1H), 2.85-2.81 (m, 2H), 2.75-2.65 (m, 2H), 2.50-2.41 (m, 1H), 2.25 (d, J= 16.5 Hz, 1H), 2.05-1.84 (m, 3H), 1.82-1.75 (m, 4H), 1.73-1.58 (m, 2H)329 I-217

(300 MHz, DMSO-d6): 7.50-7.45 (m, 2H), 7.06 (d, J = 7.8 Hz, 1H),4.63-4.58 (m, 2H), 4.30-4.25 (m, 2H), 3.49 (d, J = 7.5 Hz, 2H),3.20-3.02 (m, 3H), 2.84- 2.80 (m, 2H), 2.72 (s, 2H), 2.28-2.23 (m, 1H),2.03 (d, J = 16.5 Hz, 1H), 1.77-1.73 (m, 2H) 331 I-222

(400 MHz, DMSO-d6): 7.50-7.45 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H),3.74-3.20 (m, 8H), 3.10 (d, J = 9.6 Hz, 1H), 2.87- 2.83 (m, 2H), 2.78(d, J = 7.2 Hz, 2H), 2.29 (d, J = 16.4 Hz, 1H), 2.06 (d, J = 16.4 Hz,1H), 1.80-1.78 (m, 2H), 1.70- 1.63 (m, 2H) 333 I-211

(300 MHz, DMSO-d6): 11.09 (br s, 1H), 8.95 (br s, 1H), 7.51-7.45 (m,2H), 7.13 (d, J = 8.1 Hz, 1H), 3.25-3.16 (m, 3H), 3.08 (d, J = 9.6 Hz,1H), 2.87-2.82 (m, 2H), 2.77-2.76 (m, 2H), 2.26 (d, J = 16.2 Hz, 1H),2.02 (d, J = 16.5 Hz, 1H0, 1.81-1.76 (m, 2H), 1.02-0.97 (m, 3H) 289I-223

(300 MHz, DMSO-d6): 11.01 (br s, 1H), 9.04 (br s, 1H), 7.52-7.34 (m,2H), 7.13 (d, J = 7.8 Hz, 1H), 4.11-4.01 (m, 2H), 3.38 (s, 1H), 3.24 (d,J = 9.3 Hz, 1H), 2.85-2.78 (m, 4H), 2.37 (d, J = 16.5 Hz, 1H), 2.14 (d,J = 16.8 Hz, 1H), 1.83-1.79 (m, 2H) 343 I-212

(300 MHz, DMSO-d6): 11.10 (br s, 1H), 8.95 (br s, 1H), 7.51-7.45 (m,2H), 7.13 (d, J = 8.1 Hz, 1H), 3.22 (d, J = 9.9 Hz, 1H), 3.07 (d, J =9.6 Hz, 1H), 2.98-2.91 (m, 2H), 2.87-2.83 (m, 2H), 2.77 (s, 2H), 2.29(d, J = 16.5 Hz, 1H), 2.06 (d, J = 16.2 Hz, 1H), 1.88-1.69 (m, 3H),0.83-0.80 (m, 6H) 317 I-213

(400 MHz, DMSO-d6): 11.10 (s, 1H), 8.95 (s, 1H), 7.52-7.46 (m, 2H), 7.13(d, J = 8 Hz, 1H), 4.19-4.15 (m, 1H), 3.15 (d, J = 10 Hz, 1H), 3.03 (d,J = 9.6 Hz, 1H), 2.87-2.83 (m, 2H), 2.76-2.74 (m, 2H), 2.25 (d, J = 16.4Hz, 1H), 2.03 (d, J = 16.4 Hz, 2H), 1.80-1.76 (m, 2H), 1.05-1.02 (m, 6H)303 I-218

(300 MHz, DMSO-d6): 11.07 (br s, 1H), 8.97 (br s, 1H), 7.47-7.42 (m,2H), 7.36-7.21 (m, 5H), 7.08 (d, J = 8.1 Hz, 1H), 4.37 (s, 2H), 3.11 (d,J = 9.9 Hz, 1H), 2.96 (d, J = 9.9 Hz, 1H), 2.89-2.74 (m, 4H), 2.36 (d, J= 16.5 Hz, 1H), 2.13 (d, J = 16.5 Hz, 1H), 1.78-1.73 (m, 2H) 351

Example 35 Preparation of(R)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-205)

Step-1:(R)-1′-(Cyclobutylmethyl)-5′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylicacid

Into a 10-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of the first eluted isomerfrom Example 34, Step 6, which was assigned as methyl(R)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). This wasfollowed by the portionwise addition of NaH (60% dispersion in oil, 30mg, 0.75 mmol, 3.89 equiv) at 0° C. The mixture was stirred for 30 minat 25° C. To this was added (bromomethyl)cyclobutane (115 mg, 0.77 mmol,4 equiv). The resulting solution was stirred for 2 h at 25° C. Thereaction was then poured into 10 mL of ice/water. The resulting solutionwas extracted with 10 mL of EtOAc. The pH of the aqueous layer wasadjusted to 3 with 6N HCl. The resulting solution was extracted with3×50 mL of CH₂Cl₂, dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by normal phasechromatography on silica gel column with CH₂Cl₂/MeOH (10:1). Thecollected fractions were concentrated under vacuum to give 67 mg (crude)of the title compound as a yellow oil. MS: (ES, m/z): 314 [M+H]⁺.

Step-2:(R)-1′-(Cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 25-mL round-bottom flask was placed a solution of the productfrom Step 1, which was assigned as(R)-1′-(cyclobutylmethyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylicacid as described above, (67 mg, 0.21 mmol, 1 equiv) in DMA (3 mL). Thiswas followed by the dropwise addition of isopropyl chloroformate (135mg, 1.10 mmol, 5.15 equiv) with stirring at 0° C. NMM (128 mg, 1.27mmol, 5.92 equiv) was added to the solution dropwise with stirring at 0°C. The mixture was stirred for 30 min at 0° C. Next, a solution ofNH₂OH.HCl (75 mg, 1.08 mmol, 5.05 equiv) in DMA (2 mL) was addeddropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out and thecrude product was purified by Prep-HPLC with the following conditions:Column: XBridge Prep C18 OBD, 19×150 mm 5 μm; Mobile Phase A: Water/0.1%Formic Acid, Mobile Phase B: CH₃CN/0.1% Formic Acid; Gradient: 25% B upto 55% B in 7 min; Detector: UV 254, 220 nm. The collected fractionswere lyophilized to give 10.5 mg (15% yield) of the title compound as apink solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.17 (br s, 1H), 8.97(br s, 1H), 7.46-7.44 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 3.19-3.16 (m,3H), 3.03 (d, J=9.6 Hz, 1H), 2.84-2.80 (m, 2H), 2.78-2.72 (m, 2H),2.48-2.41 (m, 1H), 2.24 (d, J=16.4 Hz, 1H), 2.03-1.91 (m, 3H), 1.83-1.74(m, 4H), 1.68-1.60 (m, 2H). MS: (ES, m/z): 329 [M+H]⁺.

Example 36 Preparation of(R)-N-hydroxy-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-226)

Step-1: Methyl(R)-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 10-mL vial was placed a solution of the first eluted isomer fromExample 34, Step 6, which was assigned as methyl(R)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (60 mg, 0.23 mmol, 1 equiv) in DMF (5 mL). This wasfollowed by the portionwise addition of NaH (60% in oil, 56 mg, 1.40mmol, 6 equiv) at 0° C. The resulting solution was stirred for 30 min atroom temperature. Next, a solution of Et₃N (93 mg, 0.92 mmol, 4 equiv)and 3-(bromomethyl)pyridine hydrobromide (232 mg, 0.92 mmol, 4 equiv) inDMF (1 mL) were added dropwise at 0° C. The resulting solution wasstirred for 2 h at 25° C. The reaction mixture was poured into 20 mL ofwater/ice. The resulting solution was extracted with 3×20 mL of EtOAc,dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum togive 47 mg (58% yield) of the title compound as a yellow oil. MS: (ES,m/z): 351 [M+H]⁺.

Step-2:(R)-N-Hydroxy-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 25-mL round-bottom flask was placed a solution of the productfrom Step 1, which was assigned as methyl(R)-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (47 mg, 0.13 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL),and NH₂OH (50% in water, 531 mg, 8.04 mmol, 60 equiv). This was followedby the dropwise addition of 1N aq. NaOH (0.3 mL, 0.27 mmol, 2 equiv).The resulting solution was stirred for 2 h at 25° C. The solids werefiltered and the crude product was purified by Prep-HPLC with thefollowing conditions: Column: XBridge Prep C18 OBD, 19×150 mm 5 μm;Mobile Phase A: Water/0.01% NH₄HCO₃, Mobile Phase B: CH₃CN/0.01%NH₄HCO₃; Gradient: 5% B up to 20% B in 6 min; Detector: UV 254, 220 nm.The collected fractions were lyophilized to give 13.7 mg (29% yield) ofthe title compound as a brown solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm):10.90 (br s, 1H), 9.07 (br s, 1H), 8.50-8.47 (m, 2H), 7.65 (d, J=8 Hz,1H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 7.08 (d, J=8 Hz, 1H), 4.42(s, 2H), 3.15 (d, J=10 Hz, 1H), 3.00 (d, J=10 Hz, 1H), 2.90-2.74 (m,4H), 2.37 (d, J=16.4 Hz, 1H), 2.14 (d, J=16.8 Hz, 1H), 1.81-1.76 (m,2H). MS: (ES, m/z): 352 [M+H]⁺.

Example 37 Preparation of(R)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-203)

Step-1: Methyl(R)-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of the firsteluted isomer from Example 34, Step 6, which was assigned as methyl(R)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (50 mg, 0.19 mmol, 1 equiv) in CH₂Cl₂ (15 mL), Et₃N(58 mg, 0.57 mmol, 3 equiv), phenylboronic acid (48 mg, 0.39 mmol, 2equiv), Cu(OAc)₂ (38 mg, 0.21 mmol, 1 equiv), and 4 Å molecular sieves(100 mg). O₂ was introduced into the flask and the resulting solutionwas stirred overnight at 25° C. The reaction was then quenched by theaddition of 20 mL of water and diluted with 20 mL of CH₂Cl₂. The solidswere filtered out and the filtrate was extracted with 2×20 mL of CH₂Cl₂.The combined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by normal phasecolumn chromatography on silica gel with EtOAc/petroleum ether (1:3).The collected fractions were concentrated under vacuum to give 60 mg(92% yield) of the title compound as a yellow oil. MS: (ES, m/z): 336[M+H]⁺.

Step-2:(R)-N-Hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 10-mL round-bottom flask, was placed a solution of the productfrom Step 1, which was assigned as methyl(R)-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (60 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL),NH₂OH (50% in water, 709 mg, 120 equiv), and 1N aq. NaOH (14.4 mg, 0.36mmol, 2 equiv). The resulting solution was stirred for 2 h at 25° C. Thecrude product was purified by Prep-HPLC with the following conditions:Column: XBridge Prep C18 OBD, 19×150 μm 5 μm; Mobile Phase A: Water/0.1%Formic acid, Mobile Phase B: CH₃CN; Gradient: 20% B to 45% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized togive 23.9 mg (40% yield) of the title compound as a white solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.06 (s, 1H), 8.94 (s, 1H), 7.63-7.61 (m,2H), 7.52 (s, 1H), 7.47-7.44 (m, 1H), 7.35-7.31 (m, 2H), 7.14-7.08 (m,2H), 3.77-3.74 (d, J=9.6 Hz, 1H), 3.57-3.55 (d, J=9.6 Hz, 1), 2.96-2.80(m, 4H), 2.58-2.54 (d, J=16.8 Hz, 1H), 2.33-2.28 (d, J=16.8 Hz, 1H),1.89-1.85 (m, 2H). MS: (ES, m/z): 337 [M+H]⁺.

TABLE-22 The following compounds were prepared according to the methodof Example 37 with the first eluted product from Example 34, Step 6.Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-209

(400 MHz, DMSO-d6): 11.08 (s, 1H), 8.93 (s, 1H), 7.49-7.44 (m, 2H), 7.10(d, J = 8.0 Hz, 1H), 3.13 (d, J = 9.6 Hz, 1H), 2.96 (d, J = 9.6 Hz, 1H),2.83-2.60 (m, 5H), 2.25 (d, J = 16.4 Hz, 1H), 2.01 (d, J = 16.8 Hz, 1H),1.75-1.72 (m, 2H), 0.64-0.52 (m, 4H) 301 I-221

(300 MHz, DMSO-d6): 11.16 (s, 1H), 8.96 (s, 1H), 8.87 (d, J = 2.4 Hz,1H), 8.33 (d, J = 3.3 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.54 (s, 1H),7.48 (d, J = 7.8 Hz, 1H), 7.39 (m, 1H), 7.14 (d, J = 7.8 Hz, 1H), 3.82(d, J = 9.9 Hz, 1H), 3.63 (d, J = 9.9 Hz, 1H), 2.90-2.88 (m, 4H), 2.60(d, J = 16.5 Hz, 1H), 2.35 (d, J = 16.5 Hz, 1H), 1.89 (s, 2H) 338 I-227

(400 MHz, DMSO-d6): 11.11 (br s, 1H), 8.99 (br s, 1H), 7.70-7.64 (m,2H), 7.54 (s, 1H), 7.49-7.41 (m, 1H), 7.23- 7.08 (m, 3H), 3.77 (d, J =10 Hz, 1H), 3.57 (d, J = 9.6 Hz, 1H), 3.98-2.86 (m, 4H), 2.8 (d, J =16.8 Hz, 1H), 2.32 (d, J = 16.4 Hz, 1H), 1.90-1.87 (m, 2H) 355

TABLE-23 The following compounds were prepared according to the methodof Example 37, with the following modification: In Step 1, the secondeluted product from Example 34, Step 6 was used. Found (ES, m/z) Ex.Structure ¹H-NMR δ (ppm) [M + H]⁺ I-204

(300 MHz, DMSO-d6): 11.09 (s, 1H), 9.00 (s, 1H), 7.64 (d, J = 7.8 Hz,2H), 7.54 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.37-7.32 (m, 2H),7.16-7.09 (m, 2H), 3.78 (d, J = 9.9 Hz, 1H), 3.58 (d, J = 9.9 Hz, 1H),2.94-2.86 (m, 4H), 2.58 (d, J = 16.8 Hz, 1H), 2.32 (d, J = 16.8 Hz, 1H),1.91-1.86 (m, 2H) 337 I-214

(300 MHz, DMSO-d6): 11.06 (br s, 1H), 8.94 (s, 1H), 7.50-7.45 (m, 2H),7.12 (d, J = 7.8 Hz, 1H), 3.14 (d, J = 9.6 Hz, 1H), 2.97 (d, J = 9.6 Hz,1H), 2.85-2.80 (m, 2H), 2.73-2.72 (m, 1H), 2.66-2.61 (m, 2H), 2.26 (d, J= 16.2 Hz, 1H), 2.02 (d, J = 16.5 Hz, 1H), 1.77- 1.73 (m, 2H), 0.66-0.56(m, 4H) 301 I-224

(300 MHz, DMSO-d6): 11.12 (br s, 1H), 9.01 (br s, 1H), 8.88 (d, J = 1.8Hz, 2H), 8.33 (d, J = 4.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.55 (s,1H), 7.49 (d, J = 8.1 Hz, 1H), 7.42-7.37 (m, 1H), 7.15 (d, J = 8.1 Hz,1H), 3.82 (d, J = 9.9Hz, 1H), 3.63 (d, J = 9.9 Hz, 1H), 2.99-2.89 (m,4H), 2.61 (d, J = 16.8 Hz, 1H), 2.35 (d, J = 16.8 Hz, 1H), 1.92- 1.88(m,2H) 338

Example 38 Preparation of(R)-N-hydroxy-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-228)

Step-1: Methyl(R)-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Into a 10-mL sealed tube purged and maintained with an inert atmosphereof nitrogen was placed the first eluted isomer from Example 34, Step 6,which was assigned as methyl(R)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (50 mg, 0.19 mmol, 1 equiv), toluene (4 mL),4-bromopyridine (60.6 mg, 0.38 mmol, 2 equiv), RuPhos Pd G2 (15 mg, 0.02mmol, 0.1 equiv), RuPhos (18 mg, 0.04 mmol, 0.20 equiv), and Cs₂CO₃ (189mg, 0.58 mmol, 3 equiv). The resulting solution was stirred for 16 h at100° C. in an oil bath. The reaction mixture was cooled to roomtemperature. The resulting solution was poured into 20 mL of water,extracted with 2×10 mL of EtOAc, dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by preparativeTLC with CH₂Cl₂/MeOH (20:1). The collected band was dissolved inCH₂Cl₂/MeOH (20:1), filtered and was concentrated under vacuum to give60 mg (93% yield) of the title compound as a yellow oil. MS: (ES, m/z):337 [M+H]⁺.

Step-2:(R)-N-Hydroxy-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Into a 8-mL vial was placed a solution of the product from Step 1, whichwas assigned as methyl(R)-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylateas described above, (60 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL),NH₂OH (50% in water, 1.4 g, 21.43 mmol, 120 equiv) and 1N aq. NaOH (0.35mL, 0.35 mmol, 2 equiv). The resulting solution was stirred for 3 h atroom temperature. The solids were filtered out and the crude product waspurified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1% FormicAcid, Mobile Phase B: CH₃CN/0.1% Formic Acid; Gradient: 3% B up to 23% Bin 5 min; Detector: UV 220, 254 nm. The collected fractions werelyophilized with 1M HCl (1 mL) to give 23.4 mg (39% yield) of the titlecompound as the HCl salt as a pink solid. ¹H-NMR (300 MHz, DMSO-d6) δ(ppm): 11.14 (br s, 1H), 8.96 (br s, 1H), 8.67 (d, J=6.3 Hz, 2H), 8.04(d, J=6 Hz, 2H), 7.56-7.47 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 3.86 (d,J=10.2 Hz, 1H), 3.71 (d, J=10.2 Hz, 1H), 2.99-2.82 (m, 4H), 2.74 (d,J=17.1 Hz, 1H), 2.49 (d, J=16.8 Hz, 1H), 1.92-1.87 (m, 2H). MS: (ES,m/z): 338 [M+H]⁺.

TABLE-24 The following compound was prepared according to the method ofExample 38. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-229

(300 MHz, DMSO-d6): 11.10 (br s, 1H), 8.99 (br s, 1H), 8.33-8.30 (m,2H), 7.84-7.78 (m, 1H), 7.54-7.41 (m, 2H), 7.14-7.10 (m, 2H), 3.87 (s,1H), 2.92- 2.85 (m, 4H), 2.68 (d, J = 16.8 Hz, 1H), 2.41 (d, J = 17.1Hz, 1H), 1.91-1.87 (m, 2H) 338

Example 39 Preparation ofN-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-230)

Step-1: Ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate

Into a 250-mL 3-necked round-bottom flask was placed NaH (28 g, 3 equiv)in THF (800 mL) at 0° C. Then 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (50g, 232.51 mmol, 1 equiv) and diethyl oxalate (65 mL, 2 equiv) were addedat 0° C. The resulting mixture was stirred overnight at 25° C. Thereaction was then quenched by the addition of NH₄Cl. The resultingsolution was extracted with 3×500 mL of EtOAc. The organic layers werecombined and dried over anhydrous Na₂SO₄, filtered and concentratedunder vacuum. The residue was taken up in toluene (800 mL) and PTSA (1.5g, 0.05 equiv) was added. The resulting mixture was allowed to reactwith stirring, using a Dean-Stark Separator, for an additional overnightwhile the temperature was maintained at 120° C. in an oil bath. Thesolution was concentrated under vacuum. The residue was purified bynormal phase chromatography on silica gel with EtOAc/petroleum ether(1:20). The collected fractions were concentrated to give 38 g (55%yield) of the title compound as a yellow solid. MS: (ES, m/z): 297[M+H]⁺.

Step-2: Dimethyl 4-oxo-4H-chromene-2,6-dicarboxylate

Into a 150-mL pressure tank reactor, was placed ethyl6-bromo-4-oxo-4H-chromene-2-carboxylate (20 g, 67.32 mmol, 1 equiv) inMeOH (150 mL), Et₃N (28.3 mL, 3 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (2.8 g,0.05 equiv). The resulting mixture was stirred for 4 days at 80° C.under CO (g) (20 atm). The reaction mixture was cooled to roomtemperature. The solids were filtered out and the resulting mixture wasconcentrated under vacuum. The residue was purified by normal phasechromatography on silica gel with EtOAc/petroleum ether (1:10). Thecollected fractions were concentrated to give 4 g (23% yield) of thetitle compound as a white solid. MS: (ES, m/z): 263 [M+H]⁺.

Step-3: Dimethyl chromane-2,6-dicarboxylate

Into a 250-mL pressure tank reactor, was placed dimethyl4-oxo-4H-chromene-2,6-dicarboxylate (15 g, 57.20 mmol, 1 equiv),palladium on carbon (3 g, 0.2 equiv), MeOH (150 mL) and AcOH (15 mL, 10equiv). The resulting mixture was stirred for 2 days at 80° C. under H₂(g). The reaction mixture was cooled to room temperature. The solidswere filtered out and the filtrate was concentrated under vacuum. Theresidue was purified by normal phase chromatography on silica gel withEtOAc/petroleum ether (1:10). The collected fractions were concentratedto give 10 g (70% yield) of the title compound as a white solid. MS:(ES, m/z): 251 [M+H]⁺.

Step-4: Dimethyl 2-(cyanomethyl)chromane-2,6-dicarboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, were placed a solution of dimethylchroman-2,6-dicarboxylate (2 g, 7.99 mmol, 1 equiv) in THF (20 mL). Thiswas followed by the dropwise addition of LDA (10.4 mL, 1.30 equiv) withstirring at −78° C. The resulting solution was stirred for 1 h at −78°C. 2-Bromoacetonitrile (0.84 mL, 1.5 equiv) was added dropwise withstirring at −78° C. The reaction was stirred for 1 h at −60° C. Thereaction was then quenched by the addition of 20 mL of sat aq. NH₄Cl.The resulting solution was extracted with 3×50 mL of EtOAc. The organicswere combined, dried over anhydrous Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by normal phase chromatography onsilica gel with EtOAc/petroleum ether (1:3). The collected fractionswere concentrated to give 0.7 g (30% yield) of the title compound as awhite solid. MS: (ES, m/z): 290 [M+H]⁺.

Step-5: Methyl 2′-oxospiro[chroman-2,3′-pyrrolidine]-6-carboxylate

Into a 50-mL round-bottom flask were placed dimethyl2-(cyanomethyl)chroman-2,6-dicarboxylate (700 mg, 2.42 mmol, 1 equiv) inMeOH (15 mL), 7M NH₃ in MeOH (1 mL) and PtO₂ (160 mg, 0.70 mmol, 0.13equiv). H₂ (g) was introduced to the flask. The resulting mixture wasstirred overnight at room temperature. The solids were filtered out andthe filtrate was concentrated under vacuum. The residue was purified bynormal phase chromatography on silica gel with EtOAc/petroleum ether(1:1). The collected fractions were concentrated to give 0.22 g (35%yield) of the title compound as a white solid. MS: (ES, m/z): 262[M+H]⁺.

Step-6: Methyl2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxylate

Into a 25-mL round-bottom flask was placed methyl2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxylate (50 mg, 0.19 mmol,1 equiv) in DMF (5 mL), NaH (23 mg, 0.96 mmol, 3 equiv) and4-(bromomethyl)pyridine (73 mg, 0.43 mmol, 1.5 equiv). The resultingmixture was stirred for 4 h at room temperature. The reaction was thenquenched by the addition of NH₄Cl. The resulting solution was extractedwith 3×30 mL of EtOAc. The combined organics were dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum. The residue waspurified by normal phase chromatography on silica gel with CH₃Cl/MeOH(50:1). The collected fractions were concentrated to give 30 mg (45%yield) of the title compound as a light yellow solid. MS: (ES, m/z): 353[M+H]⁺.

Step-7:N-Hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide

Into a 25-mL round-bottom flask was placed a solution of methyl2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxylate(30 mg, 0.09 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), NH₂OH (50% inwater, 168 mg, 30 equiv) and 1N aq. NaOH (1.7 mL, 2 equiv). Theresulting solution was stirred for 5 h at 25° C. The pH of the solutionwas adjusted to 6 with 3N aq. HCl. The crude product was purified byPrep-HPLC with the following conditions: Column: Waters HSS C18, 2.1×50mm, 1.8 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05%TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2.0 min, hold 0.6min; Detector: UV 254 nm. The collected fractions were lyophilized togive 1.3 mg (3% yield) of the title compound as a white solid. ¹H-NMR(300 MHz, DMSO-d6) δ (ppm): 11.04 (s, 1H), 8.63-8.65 (d, 2H), 7.50-7.56(t, 2H), 7.37-7.39 (d, 2H), 6.82-6.84 (d, 1H), 4.54-4.55 (d, 2H), 2.96(s, 2H), 2.73-2.83 (d, 2H), 2.21-2.27 (m, 2H), 1.98-2.13 (m, 2H). MS:(ES, m/z): 354 [M+H]⁺.

TABLE-25 The following compounds were prepared according to the methodof Example 39, with the following modification: In Step 6, the halidecan be an iodide, a chloride, or a bromide. Found (ES, m/z) Ex.Structure ¹H-NMR δ (ppm) [M + H]⁺ I-232

(300 MHz, DMSO-d6): 11.01 (s, 1H), 7.55 (s, 1H), 7.49-7.52 (d, 1H),7.23- 7.38 (m, 4H), 6.79-6.82 (d, 1H), 4.43- 4.44 (d, 2H), 3.21-3.35 (m,2H), 2.95- 3.05 (m, 1H), 2.72-2.83 (m, 1H), 2.04- 2.27 (m, 3H),1.92-1.94 (d, 1H) 353 I-234

(300 MHz, DMSO-d6): 11.00 (s, 1H), 7.47-7.54 (m, 2H), 6.76-6.79 (d, 1H),3.81-3.86 (m, 2H), 3.38-3.50 (m, 2H), 3.23-3.35 (m, 2H), 3.10-3.13 (m,2H), 2.90 (s, 1H), 2.80 (s, 1H), 2.02-2.20 (m, 3H), 1.85-1.93 (m, 2H),1.49-1.53 (t, 2H), 1.13-1.17 (m, 2H) 361 I-237

(400 MHz, DMSO-d6): 10.99 (br s, 1H), 8.85 (br s, 1H), 7.53 (s, 1H),7.50- 7.45 (m, 1H), 6.78-6.73 (m, 1H), 3.43- 3.38 (m, 2H), 3.01-2.89 (m,1H), 2.85- 2.75 (m, 1H), 2.79 (s, 3H), 2.23-1.97 (m, 3H), 1.96-1.80 (m,1H) 277

Example 40 Preparation ofN-hydroxy-2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-231)

Step-1: Methyl2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6-carboxylate

Into a 50-mL 3-necked round-bottom flask was placed a solution of methyl2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxylate (80 mg, 0.31 mmol,1 equiv) in 1,4-dioxane (10 mL), iodobenzene (76 mg, 0.37 mmol, 1.2equiv), Pd(OAc)₂ (6.8 mg, 0.1 equiv), XantPhos (39.2 mg, 0.07 mmol, 0.2equiv) and Cs₂CO₃ (200 mg, 0.61 mmol, 2 equiv). The resulting mixturewas stirred for 3 h at 100° C. under N₂. The solids were filtered outand the filtrate was concentrated under vacuum. The residue was purifiedby normal phase chromatography on silica gel with EtOAc/petroleum ether(1:2). The collected fractions were concentrated to give 40 mg (39%yield) of the title compound as a brown solid. MS: (ES, m/z): 338[M+H]⁺.

Step-2:N-Hydroxy-2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6-carboxamide

Into a 25-mL round-bottom flask was placed a solution of methyl2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6-carboxylate (40 mg,0.12 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), NH₂OH (50% in water, 235mg, 30 equiv), and 1N aq. NaOH (0.238 mL, 2 equiv). The resultingsolution was stirred for 1 h at 25° C. The crude product was purified byPrep-HPLC with the following conditions: Column: Waters HSS C18, 2.1×50mm, 1.8 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05%TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2.0 min, hold 0.6min; Detector: UV 254 nm. The collected fractions were lyophilized togive 26.1 mg (65% yield) of the title compound as an off-white solid.¹H-NMR (300 MHz, DMSO-d6) δ (ppm): 11.02 (s, 1H), 7.70-7.23 (d, 2H),7.50-7.57 (m, 2H), 7.39-7.44 (t, 2H), 7.17-7.22 (t, 1H), 6.83-6.86 (d,1H), 3.87-3.92 (m, 2H), 2.83-2.93 (m, 2H), 2.29-2.39 (m, 2H), 2.17-2.22(t, 1H), 2.00-2.05 (t, 1H). MS: (ES, m/z): 339 [M+H]⁺.

TABLE-26 The following compound was prepared according to the method ofExample 40. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-233

(300 MHz, DMSO-d6): 11.05 (s, 1H), 8.93 (s, 1H), 8.39-8.43 (m, 1H),8.13- 8.17 (m, 1H), 7.44-7.58 (m, 3H), 6.83- 6.86 (d, 1H), 3.92-3.97 (m,2H), 2.73- 2.92 (m, 2H), 2.34-2.43 (m, 2H), 2.19- 2.29 (m, 1H),2.04-2.07 (d, 1H) 340

Example 41 Preparation ofN-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide (I-236)

Into an 8-mL vial, was placed a solution of methyl2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxylate (70 mg, 0.27 mmol,1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (in 50% water, 0.53 mL, 30equiv), and 1N aq. NaOH (0.54 mL, 2 equiv). The resulting solution wasstirred for 2 h at room temperature. The crude product was purified byPrep-HPLC with the following conditions: Column: Sunfire C18, 19×150 mm,5 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: CH₃CN/0.05% TFA;Gradient: 5% B to 65% B in 8 min; Detector: UV 254 nm. The collectedfractions were lyophilized to give 22.8 mg (32% yield) as a pink solid.¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.99 (s, 1H), 8.88 (m, 1H), 8.06 (s,1H), 7.52-7.46 (m, 2H), 6.79-6.77 (d, J=8.0 Hz, 1H), 3.31-3.28 (m, 2H),2.97-2.93 (m, 1H), 2.79-2.73 (m, 1H), 2.21-2.19 (m, 2H), 2.17-2.00 (m,1H), 1.89-1.83 (m, 1H). MS: (ES, m/z): 263 [M+H]⁺.

Example 42 Preparation ofN-hydroxy-1′-isopropyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-235)

Step-1: Methyl1′-isopropyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxylate

Into a 25-mL round-bottom flask was placed a solution of methyl2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxylate (100 mg, 0.38 mmol,1 equiv) in CH₃CN (6 mL), 2-iodopropane (326 mg, 1.92 mmol, 5 equiv),Cs₂CO₃ (375 mg, 1.15 mmol, 3 equiv). The resulting solution was stirredfor 18 h at 70° C. The resulting mixture was concentrated under vacuum.The residue was dissolved in 20 mL of EtOAc. The resulting mixture waswashed with 2×15 mL of H₂O. The organics were dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by normalphase chromatography on silica gel with EtOAc/petroleum ether (1:1). Thecollected fractions were concentrated to give 44.2 mg (38% yield) of thetitle compound as a solid. MS: (ES, m/z): 304 [M+H]⁺.

Step-2:N-Hydroxy-1′-isopropyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide

Into an 8-mL vial, was placed a solution of methyl1′-isopropyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxylate (44.2mg, 0.15 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), NH₂OH (50% in water,0.29 mL, 30 equiv), and 1N aq. NaOH (0.29 mL, 2 equiv). The resultingsolution was stirred for 2.5 h at room temperature. The crude productwas purified by Prep-HPLC with the following conditions: Column: XbridgeC18, 19×150 mm, 5 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B:CH₃CN/0.05% TFA; Flow rate: 25 mL/min; Gradient: 5% B to 57% B in 7 min;Detector: UV 254 nm, 220 nm. The collected fractions were lyophilized togive 15.8 mg (36% yield) of the title compound as a pink solid. ¹H-NMR(400 MHz, DMSO-d6) δ (ppm): 11.00 (br s, 1H), 8.87 (s, 1H), 7.53-7.47(s, 2H), 6.79-6.76 (d, J=12 Hz, 1H), 4.11 (m, 1H), 3.36-3.35 (m, 1H),3.30-3.28 (m, 1H), 2.98-2.88 (m, 1H), 2.79-2.73 (m, 1H), 2.18-1.99 (m,3H), 1.88-1.83 (m, 1H), 1.13-1.08 (m, 6H). MS: (ES, m/z): 305 [M+H]⁺.

Example 43 Preparation ofN-hydroxy-1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-1)

Step-1: tert-Butyl6-bromo-4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate

1-(5-Bromo-2-hydroxyphenyl)ethan-1-one (10.0 g, 45.5 mmol), tert-butyl4-oxopiperidine-1-carboxylate (9.27 g, 46.5 mmol) and pyrrolidine (1.91mL, 23.3 mmol) were combined in 75 mL of MeOH and refluxed for 12 h.After cooling down to room temperature the reaction mixture wasconcentrated to dryness and purified by normal phase chromatography onsilica gel (EtOAc/hexanes gradient). After purification 17.1 g (92%yield) of the title compound was obtained. ¹H NMR (300 MHz, CDCl₃) δ(ppm): 7.96 (d, J=2.5 Hz, 1H), 7.55 (dd, J₁=8.8 Hz, J₂=2.5 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 3.86 (br s, 2H), 3.20-3.10 (m, 2H), 2.71 (s, 2H),2.05-1.90 (m, 2H), 1.70-1.55 (m, 2H), 1.45 (s, 9H). MS: (ES, m/z):296/298 [M−Boc]⁺.

Step-2: tert-Butyl6-bromo-4-hydroxyspiro[chromane-2,4′-piperidine]-1′-carboxylate

Sodium borohydride (0.120 g, 3.15 mmol, 1 equiv) was added to asuspension of tert-butyl6-bromo-4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (1.25 g,3.15 mmol, 1 equiv) in EtOH (25 mL). The reaction was stirred at roomtemperature for 16 h. The reaction was concentrated under vacuum toafford 1 g (crude) of the title compound and was used without furtherpurification.

Step-3: 1′-(tert-Butyl) 6-methylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxylate

To a solution of tert-butyl6-bromo-4-hydroxyspiro[chromane-2,4′-piperidine]-1′-carboxylate (1 g,2.51 mmol, 1 equiv) in CH₂Cl₂ (14.5 ml) was added TFA (6.38 ml, 83 mmol,33.07 equiv) and triethylsilane (3.21 ml, 20.09 mmol, 8 equiv). Thereaction was concentrated to afford 882 mg of the title compound, whichwas used without further purification.

Step-4: 1′-(tert-Butyl) 6-methylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxylate

To a solution of tert-butyl6-bromospiro[chromane-2,4′-piperidine]-1′-carboxylate (249 mg, 0.651mmol, 1 equiv) in THF (5 mL) cooled to −78° C. (dry ice/acetone bath),was added n-Butyl lithium (1.6M, 0.602 mL, 0.964 mmol, 1.48 equiv). Theresulting mixture was stirred at −78° C. for 45 min when methylchloroformate (1.0 mL, 13.02 mmol, 20 equiv) was added. The resultingmixture was stirred and slowly warmed to room temperature and thenstirred for 1 h. The reaction was concentrated under reduced pressure.The light pink residue was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The organic layers were combinedand dried over Na₂SO₄, concentrated and purified by normal phasechromatography on silica gel (10-50% EtOAc/hexanes) to provide 243 mg ofthe title compound. MS: (ES, m/z): 362 [M+H]⁺.

Step-5: Methyl spiro[chromane-2,4′-piperidine]-6-carboxylate

To a solution of 1′-(tert-butyl) 6-methylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxylate (243 mg, 0.672 mmol,1 equiv) in CH₂Cl₂ (0.5 mL) was added TFA (0.259 mL, 3.36 mmol, 5equiv). The reaction mixture was stirred at room temperature for 40 min.The reaction mixture was then concentrated under vacuum and azeotropedwith toluene 3 times. The crude mixture was used in the next stepwithout further purification. MS: (ES, m/z): 262 [M+H]⁺.

Step-6: Methyl1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]-6-carboxylate

Methyl spiro[chromane-2,4′-piperidine]-6-carboxylate (126.3 mg, 0.336mmol, 1 equiv) was combined with Et₃N (0.094 mL, 0.671 mmol, 2 equiv)and 4-methoxybenzaldehyde (0.041 mL, 0.336 mmol, 1 equiv) in DCE (2.0mL). The reaction was stirred at room temperature for 1.5 h. ThenNaBH(OAc)₃ (92 mg, 0.436 mmol, 1.3 equiv) was added and the reaction wasallowed to stir at room temperature for 16 h. The reaction mixture wasdirectly purified by normal phase chromatography on silica gel (10%-60%EtOAc/hexanes) to afford 37 mg (28% yield) of the title compound. MS:(ES m/z) 382 [M+H]⁺.

Step-7:N-hydroxy-1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]-6-carboxamide

Methyl 1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]-6-carboxylate(36 mg, 0.095 mmol, 1 equiv) was dissolved in a solution of THF/MeOH(4:1, 1.25 mL). NH₂OH (50% in water, 0.263 mL, 8.59 mmol, 90 equiv) wasadded followed by 2N aq. NaOH (0.095 mL, 2 equiv). The reaction wasallowed to stir at room temperature for 18 h and was purified directlyby reverse-phase chromatography using the following conditions: Column:XTerra Prep MS C18 OBD, 5 μm, 19×100 mm; Mobile Phase A: Water/0.05%Formic Acid, Mobile Phase B: CH₃CN/0.05% Formic Acid; Flow rate: 20mL/min; Gradient: 15% B to 85% B in 10 min; Detector: UV 254 nm, 220 nm.Combined fractions were lyophilized to afford 30 mg (83% yield) of thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ (PPM): 8.26-8.58 (m, 1H),7.39-7.67 (m, 4H), 6.87-7.15 (m, 3H), 4.30 (br s, 2H), 3.82 (s, 3H),3.27-3.44 (m, 6H), 2.82-3.02 (m, 2H), 1.87-2.20 (m, 6H). MS: (ES m/z)383 [M+H]⁺.

TABLE-27 The following compound was prepared according to the method ofExample 43. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ II-2

(300 MHz, CD₃OD): 8.08-8.22 (m, 2H), 7.40-7.71 (m, 4H), 7.29 (br dd, J =5.9, 2.9 Hz, 2H), 6.67-6.97 (m, 1H), 4.12 (s, 2H), 3.32 (dt, J = 3.2,1.6 Hz, 6H), 2.75-3.01 (m, 4H), 1.80-1.96 (m, 4H) 393

Example 44 Preparation of1′-(cyclohexanecarbonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-3)

Step-1: Methyl1′-(cyclohexanecarbonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate

To a solution of methyl spiro[chromane-2,4′-piperidine]-6-carboxylate(78 mg, 0.196 mmol, 1 equiv) in CH₂Cl₂ (1 mL) was added cyclohexanecarboxylic acid (26 mg, 0.206 mmol, 1.05 equiv), DIEA (0.137 mL, 0.589mmol, 3 equiv) and HBTU (86 mg, 0.226 mmol, 1.50 equiv). The reactionwas stirred at room temperature for 18 h. The reaction mixture wasconcentrated and purified by normal phase chromatography on silica gel(10%-50% EtOAc/hexanes) to afford 57 mg (78% yield) of the titlecompound. MS: (ES, m/z): 372 [M+H]⁺.

Step-2:1′-(Cyclohexanecarbonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide

Methyl1′-(cyclohexanecarbonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate(57 mg, 0.154 mmol, 1 equiv) was dissolved in a solution of THF/MeOH(4:1, 1.25 mL). NH₂OH (50% in water, 0.801 mL, 13.07 mmol, 85 equiv) wasadded, followed by 2N aq. NaOH (0.154 mL, 2 equiv). The reaction wasstirred at room temperature for 18 h and was purified directly byreverse-phase chromatography using the following conditions: Column:XTerra Prep MS C18 OBD 5 μm, 19×100 mm; Mobile Phase A: Water/0.05%Formic Acid, Mobile Phase B: CH₃CN/0.05% Formic Acid; Flow rate: 20mL/min; Gradient: 15% B to 85% B in 10 min; Detector: UV 254 nm, 220 nm.Combined fractions were lyophilized to afford 18 mg (31% yield) of thetitle compound. ¹H NMR (300 MHz, DMSO-d6) δ (ppm): 10.92 (br s, 1H),8.81 (s, 1H), 7.17-7.52 (m, 2H), 6.59-6.85 (m, 1H), 4.02 (br d, J=13.2Hz, 1H), 3.67 (br d, J=14.1 Hz, 1H), 2.93 (br t, J=11.6 Hz, 2H),2.60-2.78 (m, 2H), 1.67-1.85 (m, 3H), 1.49-1.67 (m, 7H), 0.97-1.33 (m,6H). MS: (ES, m/z): 373 [M+H]⁺.

TABLE-28 The following compound was prepared according to the method ofExample 44. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ II-4

397

Example 45 Preparation ofN-hydroxy-1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-5)

Step-1: Methyl1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate

Methyl spiro[chromane-2,4′-piperidine]-6-carboxylate (75.8 mg, 0.189mmol, 1 equiv) was combined with DIEA (0.115 mL, 0.660 mmol, 3.5 equiv)in THF (2.0 ml). After several min, 4-methoxybenzene-1-sulfonyl chloride(47 mg, 0.226 mmol, 1.20 equiv) was added and the resulting mixture wasleft to stir at room temperature for 16 h. The reaction mixture waspartitioned between sat. aq. NaHCO₃ and EtOAc. Water was added todissolve salts. The organic phase was separated and the aqueous layerwas extracted with several portions of EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The resulting residue was purified by normal phasechromatography on silica gel to afford 68 mg (84% yield) of the titlecompound. MS: (ES, m/z) 431 [M+H]⁺.

Step-2:N-Hydroxy-1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide

Methyl1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate(63 mg, 0.147 mmol, 1 equiv) was dissolved in a solution of THF/MeOH(4:1, 1.25 mL). NH₂OH (50% in water, 0.76 mL, 12.47 mmol, 85 equiv) wasadded, followed by 1N aq. NaOH (0.015 mL, 2 equiv). The reaction wasallowed to stir at room temperature for 2 h and was directly purified byreverse-phase chromatography using the following conditions: Column:XTerra Prep MS C18 OBD, 5 μm, 19×100 mm; Mobile Phase A: Water/0.05%Formic Acid, Mobile Phase B: CH₃CN/0.05% Formic Acid; Flow rate: 20mL/min; Gradient: 15% B to 85% B in 10 min; Detector: UV 254 nm, 220 nm.Combined fractions were lyophilized to afford 14 mg (22% yield) of thetitle compound. ¹H NMR (300 MHz, DMSO-d6) δ (ppm): 10.90 (br s, 1H),8.80 (s, 1H), 7.59-7.67 (m, 2H), 7.41-7.59 (m, 1H), 7.35 (dd, J=8.4, 2.2Hz, 1H), 6.99-7.15 (m, 2H), 6.51 (d, J=8.5 Hz, 1H), 3.81 (s, 3H),3.32-3.40 (m, 2H), 2.65 (br t, J=6.3 Hz, 2H), 2.51 (br t, J=10.8 Hz,2H), 1.38-1.76 (m, 6H). MS: (ES, m/z) 432 [M+H]⁺.

Example 46 Preparation of1′-(cyclohexylsulfonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-6)

Step-1: Methyl1′-(cyclohexylsulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of methyl3,4-dihydrospiro[1-benzopyran-2,4′-piperidine]-6-carboxylate (70 mg,0.24 mmol, 1 equiv) in CH₂Cl₂ (2 mL). This was followed by the additionof Et₃N (95 mg, 0.94 mmol, 4 equiv) dropwise with stirring at 0° C. Tothis was added cyclohexanesulfonyl chloride (74 mg, 0.41 mmol, 1.73equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The residue was purified bypreparative TLC with EtOAc/petroleum ether (1:2). The collectedfractions were combined and concentrated under vacuum to afford 60 mg(63% yield) of the title compound as a yellow solid. MS: (ES, m/z) 408[M+H]⁺.

Step-2:1′-(Cyclohexylsulfonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of methyl1′-(cyclohexylsulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate (60mg, 0.15 mmol, 1 equiv) in THF/MeOH (1.5 mL), NH₂OH (35.12 mmol, 234equiv), and aq. 1N NaOH (0.29 mL, 2 equiv). The resulting solution wasstirred for 7 h at room temperature. The crude product was purified byPrep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B:CH₃CN/0.05% TFA; Gradient: 10% B to 80% B in 7 min; Detector: UV 254 nm,220 nm. The product fractions were dried by lyophilization to afford 4.9mg (6% yield) of the title compound as a orange solid. ¹H NMR (400 MHz,DMSO-d6) δ (ppm): 11.00 (br s, 1H), 8.90 (br s, 1H), 7.55 (s, 1H), 7.51(m, 2H), 6.85 (d, J=8 Hz, 1H), 3.50 (m, 2H), 3.24-3.10 (m, 3H), 2.78 (t,J=6.8 Hz, 2H), 2.02 (m, 2H), 1.86-1.62 (m, 9H), 1.42-1.11 (m, 5H) 11.00(br s, 1H), 8.90 (br s, 1H), 7.55 (s, 1H), 7.51 (m, 2H), 6.85 (d, J=8Hz, 1H), 3.50 (m, 2H), 3.24-3.10 (m, 3H), 2.78 (t, J=6.8 Hz, 2H), 2.02(m, 2H), 1.86-1.62 (m, 9H), 1.42-1.11 (m, 5H). MS: (ES, m/z): 409[M+H]⁺.

Example 47 Preparation ofN6-hydroxy-N1′-phenylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxamidedicarboxamide(II-7)

Step-1: Methyl1′-(phenylcarbamoyl)spiro[chromane-2,4′-piperidine]-6-carboxylate

Into a 100-mL round-bottom flask was placed a solution of methylspiro[chromane-2,4′-piperidine]-6-carboxylate (70 mg, 0.24 mmol, 1equiv) in CH₂Cl₂ (10 mL), This was followed by the addition of Et₃N(81.26 mg, 0.80 mmol, 3 equiv) and isocyanatobenzene (40 mg, 0.34 mmol,1.5 equiv). The resulting solution was stirred for 2 h at 0° C. Theresulting mixture was concentrated under vacuum and the residue waspurified by normal phase chromatography on silica gel withEtOAc/petroleum ether (1:3). The collected fractions were concentratedto give 72 mg (81% yield) of the title compound as a light yellow solid.MS: (ES, m/z): 381 [M+H]⁺.

Step-2:N6-Hydroxy-N1′-phenylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxamidedicarboxamide

Into a 100-mL round-bottom flask was placed a solution of methyl1′-(phenylcarbamoyl)spiro[chromane-2,4′-piperidine]-6-carboxylate (72mg, 0.19 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% in water,0.5 mL, 60 equiv), and 1N aq. NaOH (0.25 mL, 2 equiv). The resultingsolution was stirred for 6 h at room temperature. The crude product waspurified by Prep-HPLC with the following conditions: Column: Waters HSSC18, 2.1×50 mm, 1.8 μm; Mobile Phase, A: Water/0.05% TFA, Mobile PhaseB: CH₃CN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2min, hold 0.6 min; Detector: UV 254 nm. The collected fractions werelyophilized to give 22.1 mg (31% yield) of the title compound as a pinksolid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.99 (br s, 1H), 8.54 (s,1H), 7.45-7.56 (m, 4H), 7.21-7.25 (d, J=8 Hz, 2H), 6.83-6.90 (m, 2H),3.90-3.86 (m, 2H), 3.28-3.22 (t, J=11.2 Hz, 2H), 2.80-2.77 (t, J=6.4 Hz,2H), 1.86-1.83 (t, J=6.8 Hz, 2H), 1.75-1.59 (m, 4H) MS: (ES, m/z): 382[M+H]⁺.

Example 48 Preparation of1′-cyclohexyl-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-8)

Step-1: Methyl1′-cyclohexylspiro[chromane-2,4′-piperidine]-6-carboxylate

Into a 100-mL round-bottom flask was placed a solution of methylspiro[chromane-2,4′-piperidine]-6-carboxylate (50 mg, 0.17 mmol, 1equiv) in CH₂Cl₂ (5 mL). This was followed by the addition ofcyclohexanone (18.77 mg, 0.19 mmol, 1 equiv) and NaBH(OAc)₃ (60.9 mg,0.29 mmol, 1.5 equiv). The resulting solution was stirred for 3 days atroom temperature. The resulting mixture was concentrated under vacuum.The residue was purified by reverse-phase chromatography using thefollowing conditions: C18 column; Mobile Phase A: Water/0.05% TFA,Mobile Phase B: CH₃CN/0.05% TFA; Gradient: 3% B to 50% B in 30 min. Thecollected fractions were concentrated to give 35 mg (61% yield) of thetitle compound as a light yellow oil. MS: (ES, m/z): 344 [M+H]⁺.

Step-2:1′-Cyclohexyl-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide

Into a 100-mL round-bottom flask was placed a solution of methyl1′-cyclohexylspiro[chromane-2,4′-piperidine]-6-carboxylate (35 mg, 0.10mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% in water, 0.7 mL,60 equiv), and 1N aq. NaOH (0.3 ml, 7.50 mmol, 2 equiv). The resultingsolution was stirred for 8 h at room temperature. The crude product waspurified by Prep-HPLC with the following conditions: Column: Waters HSSC18, 2.1×50 mm, 1.8 μm; Mobile Phase A: Water/0.05% TFA, Mobile Phase B:CH₃CN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2min, hold 0.6 min; Detector: UV 254 nm. The collected fractions werelyophilized to give 10.9 mg (22% yield) of the title compound as a pinksolid. ¹H-NMR (300 MHz, DMSO-d6) δ (ppm): 11.02 (br s, 1H), 9.25 (br s,1H), 8.90 (br s, 1H), 7.58-7.52 (m, 2H), 6.90-6.80 (m, 1H), 3.41-3.22(m, 3H), 3.14-3.10 (m, 3H), 2.82-2.78 (t, J=6.6 Hz, 2H), 2.27-2.05 (m,3H), 1.97-1.82 (m, 7H), 1.65-1.61 (m, 1H), 1.49-1.22 (m, 4H), 1.17-1.09(m, 1H). MS: (ES, m/z): 345 [M+H]⁺.

Example 49 Preparation ofN-hydroxy-1′-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-9)

Step-1:(1H-Imidazol-1-yl)(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-yl)methanone

In a 20-mL scintillation vial, 1,1′-carbonyldiimidazole (236 mg, 1.453mmol, 1.09 equiv) was taken up in THF (10 mL) and2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran](250 mg, 1.321 mmol, 1equiv) was added. The resulting solution was heated at 50° C. withagitation for 3 h. The reaction was cooled to ambient temperature, andthen concentrated to dryness. The residue was dissolved in 20 mL ofCH₂Cl₂ and washed with 20 mL of brine. The organic layer was passedthrough an Isolute© phase separator, and then concentrated to dryness toafford the title compound as a white solid which was used withoutfurther purification. MS: (ES, m/z): 284 [M+H]⁺.

Step-2:3-Methyl-1-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)-1H-imidazol-3-iumiodide

In a 20-mL scintillation vial(1H-imidazol-1-yl)(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-yl)methanone(400 mg, 1.412 mmol, 1 equiv) was taken up in CH₃CN (10 mL). CH₃I (0.53mL, 8.47 mmol, 5.96 equiv) was added and the reaction was stirred atambient temperature for 24 h. The reaction was concentrated to drynessto afford the title compound as a yellow solid which was used withoutfurther purification. MS: (ES, m/z): 299 [M−I+H]⁺.

Step-3: Methyl1′-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)spiro[chromane-2,4′-piperidine]-6-carboxylate

In a 20-mL scintillation vial3-methyl-1-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)-1H-imidazol-3-iumiodide (30 mg, 0.071 mmol, 1 equiv) and methylspiro[chromane-2,4′-piperidine]-6-carboxylate (18 mg, 0.071 mmol, 1equiv) were taken up in CH₃Cl (2 mL). Et₃N (0.029 ml, 0.212 mmol, 3equiv) was added. The resulting solution was stirred at ambienttemperature for 18 h. The reaction was diluted with 10 mL of CH₂Cl₂ andwashed with 20 mL of brine. The organic layer was passed through anIsolute© phase separator, and then concentrated to dryness to afford thetitle compound as an orange oil which was used without furtherpurification. MS: (ES, m/z): 477 [M+H]⁺.

Step-4:N-Hydroxy-1′-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide

Into a 20-mL scintillation vial was placed a solution of methyl2-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-ylcarbonyl)-5-thia-2-azaspiro[3.4]octane-7-carboxylate5,5-dioxide (30 mg, 0.069 mmol, 1 equiv) in THF/MeOH (1:1, 2 mL), NH₂OH(50% in water, 0.5 mL, 7.57 mmol, 110 equiv), and 1N aq. NaOH (0.5 mL,0.5 mmol, 7.24 equiv). The resulting solution was stirred for 2 h atambient temperature and concentrated to dryness. The crude product waspurified by Prep-HPLC using the following conditions: Column: XBridgePrep C18 OBD 5 μm, 19×50 mm; Mobile Phase A: Water/0.05% Formic acid,Mobile Phase B: CH₃CN/0.05% Formic Acid; Flow Rate: 23 mL/min; Gradient:15% B to 65% B in 8 min; Detector: UV 254 nm, 220 nm. The collectedfractions were lyophilized to obtain 5 mg (16% yield) of the titlecompound as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ (ppm): 11.00(s, 1H), 8.89 (s, 1H), 8.36 (s, 1H), 7.39-7.63 (m, 2H), 7.12-7.30 (m,2H), 7.03 (d, J=8.21 Hz, 1H), 6.78-6.97 (m, 2H), 3.83 (s, 4H), 3.44-3.58(m, 4H), 2.75 (br d, J=15.24 Hz, 4H), 1.73-1.89 (m, 6H), 1.54 (s, 2H).MS: (ES, m/z): 478 [M+H]⁺.

Example 50 Preparation of1′-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-1)

Step-1: Methyl3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

A solution ofmethyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(0.100 g, 0.386 mmol, 1 equiv) in 3 mL of THF was cooled to −10° C.(ice/acetone) when borane-THF complex (1M in THF; 0.58 mL, 0.58 mmol,1.5 equiv) was added drop wise over 5 min. The mixture was stirred at−10° C. for 5 min, then heated up to 52° C. for about 7 days and anadditional 0.5 eq borane-THF complex was added after 24 and 48 h; THFwas added as needed to maintain volume. The resulting mixture was cooledto room temperature and quenched with 0.3 mL 2 N HCl, heated to 52° C.for 1 h, then concentrated. The residue was loaded onto a 10 g (70 mL)SCX-2 cartridge with MeOH (with some CH₂Cl₂), flushed with MeOH (withsome CH₂Cl₂), and eluted with 2 M NH₃ in MeOH (with some CH₂Cl₂). Thefractions from the NH₃ elution were combined and concentrated.Purification by silica gel chromatography with CH₂Cl₂/MeOH/NH₄OH(90/20/1) afforded 134 mg (50% yield) of the title compound. ¹H NMR (300MHz, DMSO-d6) δ (ppm): 7.73-7.63 (m, 2H), 7.23-7.14 (m, 1H), 3.82 (s,3H), 3.12-3.05 (dd, 2H), 2.90-2.62 (m, 6H), 2.50 (br s, 1H), 1.78-1.45(m, 4H). MS: (APCI, m/z): 246 [M+H]⁺.

Step-2: Methyl1′-((1H-benzo[d]imidazol-2-yl)methyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

To a 20 mL vial was added methyl3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate (0.045g, 0.183 mmol, 1 equiv), K₂CO₃ (0.051 g, 0.367 mmol, 2 equiv) and DMF (1mL). Next, 2-(chloromethyl)-1H-benzo[d]imidazole (0.035 g, 0.211 mmol,1.15 equiv) was added and the mixture was stirred at 50° C. overnight.Water was added to the reaction mixture and extracted with two portionsof EtOAc. The organic layers were combined and dried over anhydrousNa₂SO₄, filtered and concentrated. Purification by column chromatographyon silica gel (0-5% MeOH/CH₂Cl₂) afforded 39 mg (57% yield) of the titlecompound as a colourless glassy solid. MS: (ES, m/z): 376 [M+H]+.

Step-3:1′-((1H-Benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Methyl1′-((1H-benzo[d]imidazol-2-yl)methyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(0.039 g, 0.104 mmol, 1 equiv) was dissolved in a solution of THF/MeOH(4:1, 1.38 mL). Hydroxylamine (50% in water, 0.58 mL, 9.4 mmol, 90equiv) was added followed by 1N aq. NaOH (0.157 mL, 3 equiv). Thereaction was stirred at room temperature for 1 h and was purifieddirectly by reverse-phase chromatography using the following conditions:Column: XTerra Prep MS C18 OBD 5 μm, 19×100 mm; Mobile Phase A:Water/0.05% Formic Acid, Mobile Phase B: CH₃CN/0.05% Formic Acid; Flowrate: 20 mL/min; Gradient: 15% B to 85% B in 10 min; Detector: UV 254nm, 220 nm. Combined fractions were lyohpilized to afford 0.016 g (41%yield) of the title compound. ¹H NMR (300 MHz, CD₃OD) δ (ppm): 8.29 (s,2H), 7.58 (br dd, J=5.9, 3.2 Hz, 3H), 7.39-7.49 (m, 2H), 7.21-7.34 (m,2H), 7.04-7.18 (m, 1H), 4.28 (br s, 2H), 3.29-3.35 (m, 4H), 2.77-3.02(m, 8H), 1.81-1.99 (m, 4H). MS: (ES, m/z): 377 [M+H]⁺.

TABLE-29 The following compound was prepared according to the method ofExample 50. Found (ES, m/z) Ex. Structure ¹H-NMR δ (ppm) [M + H]⁺ I-2

(300 MHz, CD₃OD): 8.47 (s, 1H), 7.34-7.69 (m, 3H), 7.11-7.29 (m, 3H),6.88 (d, J = 8.5 Hz, 2H), 3.76 (s, 3H), 3.46-3.64 (m, 2H), 3.16-3.46 (m,6H), 2.87-3.14 (m, 4H), 1.83-2.11 (m, 4H) 381

Example 51 Preparation ofN-hydroxy-1′-(4-methoxybenzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-3)

Step-1: Methyl1′-(4-methoxybenzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-7-carboxylate

Methyl 3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate(0.043 g, 0.177 mmol, 1 equiv) was combined with Et₃N (0.025 mL, 0.179mmol, 1 equiv) and 4-methoxybenzaldehyde (0.024 mL, 0.195 mmol, 1.1equiv) in DCE (2.0 mL). The reaction was stirred at room temperature for1 hour. Then NaBH(OAc)₃ (0.049 g, 0.23 mmol, 1.3 equiv) was added andthe reaction was stirred at room temperature for 16 h. The reactionmixture was quenched with sat. aq. NaHCO₃ and the organic layer wasseparated and directly purified by normal phase chromatography on silicagel (30% to 100% EtOAc/hexanes) to afford 0.045 g (70% yield) of thetitle compound as a colorless, glassy solid. MS: (ES, m/z): 366 [M+H]⁺.

Step-2:N-Hydroxy-1′-(4-methoxybenzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide

Methyl1′-(4-methoxybenzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-7-carboxylate(0.045 g, 0.123 mmol, 1 equiv) was dissolved in a solution of THF/MeOH(4:1, 1.25 mL). Hydroxylamine (50% in water, 0.68 mL, 11.1 mmol, 90equiv) was added followed by 2N aq. NaOH (0.185 mL, 3 equiv). Thereaction was stirred at room temperature for 48 h and was purifieddirectly by reverse-phase chromatography using the following conditions:Column: XTerra Prep MS C18 OBD 5 μm, 19×100 mm; Mobile Phase A:Water/0.05% Formic Acid, Mobile Phase B: CH₃CN/0.05% Formic Acid; Flowrate: 20 mL/min; Gradient: 15% B to 85% B in 10 min; Detector: UV 254nm, 220 nm. Combined fractions were lyohpilized to afford 27 mg (61%yield) of the title compound. ¹H NMR (300 MHz, CD₃OD) δ (ppm): 8.44 (s,2H), 7.37-7.56 (m, 4H), 7.14 (d, J=7.9 Hz, 1H), 6.84-7.09 (m, 2H), 4.32(s, 2H), 3.79 (s, 3H), 3.10-3.61 (m, 8H), 2.84-3.08 (m, 4H), 1.86-2.11(m, 4H). MS: (ES, m/z): 367 [M+H]⁺.

Example 52 Small Molecule X-ray Crystallography Experiment for methyl(R)-1′-[(4-methanesulfonylphenyl)methyl]-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate

Low-temperature diffraction data (co-scans) were collected on a RigakuMicroMax-007HF diffractometer coupled to a Saturn994+ CCD detector withCu Kβ (λ=1.54178 Å). All structures were solved by direct methods andwere refined against F² on all data by full-matrix least squares. Allnon-hydrogen atoms were refined anisotropically. Hydrogen atoms wereincluded in the model at geometrically calculated positions and refinedusing a riding model. The isotropic displacement parameters of allhydrogen atoms were fixed to 1.2 times the U value of the atoms to whichthey are linked (1.5 times for methyl groups). All atoms shown aredepicted with 50% thermal contours. The hydrogen atoms are shown asarbitrary spheres. Carbon atoms C11 and C34 both have R stereochemistry(FIG. 1).

TABLE 30 Crystal data and structure refinement for methyl (R)-1′-[(4-methanesulfonylphenyl)methyl]-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate. Empirical formulaC₂₃H₂₅NO₅S Formula weight 427.50 Temperature 93(2) K Wavelength 1.54187Å Crystal system Monoclinic Space group P 2₁ Unit cell dimensions a = α= 19.8815(6) Å 90° b = β = 5.6009(2) Å 113.941(8)° c = γ = 20.4656(14) Å90° Volume 2082.9(2) Å³ Z 4 Density (calculated) 1.363 Mg/m³ Absorptioncoefficient 1.680 mm⁻¹ F(000) 904 Crystal size 0.140 × 0.040 × 0.010 mm³Crystal color and habit Colorless Plate Diffractometer Rigaku Saturn944+ CCD Θ range for data 2.362 to 68.068°. collection Index ranges −21≦ h ≦ 22, −6 ≦ k ≦ 6, −24 ≦ l ≦ 23 Reflections collected 34368Independent reflections 7110 [R(int) = 0.1679] Observed reflections 3779(I > 2σ (I)) Completeness 97.6% to θ = 67.687° Absorption correctionSemi-empirical from equivalents Max. and min. 0.983 and 0.775transmission Solution method SHELXL-2014/7 (Sheldrick, 2014) Refinementmethod SHELXL-2014/7 (Sheldrick, 2014) Data/restraints/ 7110/1/545parameters Goodness-of-fit on F² 0.933 Final R indices R1 = 0.0633, wR2= 0.1111 [I > 2σ(I)] R indices (all data) R1 = 0.1253, wR2 = 0.1362Absolute structure 0.05(3) parameter Largest diff. peak and 0.381 and−0.629 e.Å⁻³ hole

Example 53 In vitro Histone Deacetylase Assay

The enzymatic HDAC6 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC6 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384 well plates in a total volumeof 25 μL in a reaction buffer composing: 100 mM HEPES, pH7.5, 25 mM KCl,0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (from compounds)2 μM of the fluorescently labeled peptide substrate and enzyme. Theenzyme was added at a final concentration of 1 nM. The peptide substrateRHKK(Ac)—NH2 was used. The compounds were tested at 12 concentrationsspaced by 3× dilution intervals. Negative control samples (0%-inhibitionin the absence of inhibitor) and positive control samples(100%-inhibition) were assembled in replicates of four in each assayplate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (Pinh) is determinedusing the following equation:

Pinh=(PSR0%−PSRinh)/(PSR0%−PSR100%)*100, where PSRinh is the product sumratio in the presence of inhibitor, PSR0% is the average product sumration in the absence of inhibitor and PSR100% is the average productsum ratio in 100%-inhibition control samples. The IC50 values ofinhibitors were determined by fitting the %-inhibition curves with 4parameter dose-response model using XLfit 4 software.

As set forth in Table-31, below, IC₅₀ values are defined as follows:IC50≦0.1 μM (+++); IC50>0.1 μM and ≦0.5 μM (++); IC50>0.5 μM (+).

TABLE 31 Inhibitory Concentration (IC50) Values for RepresentativeCompounds against HDAC6 HDAC6 ac- ChemDraw Name Number tivity range1′-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3,4-dihydro-1H- (I-1)+++ spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamideN-hydroxy-1′-(4-methoxyphenethyl)-3,4-dihydro-1H- (I-2) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamideN-hydroxy-1′-(4-methoxybenzyl)-3,4-dihydro-1H- (I-3) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamideN-hydroxy-1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H- (I-4) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide1′-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-5) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide1′-(3,4-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-6) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide1′-(cyclohexylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-7) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamideN-hydroxy-1′-(4-methylbenzyl)-2′-oxo-3,4-dihydro-1H- (I-8) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide1′-(3-(dimethylamino)propyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-9) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H- (I-10) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H- (I-11) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2- (I-12) ++yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide (S)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-(I-13) +++yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide (R)-N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)-3,4-dihydro-1H-(I-14) + spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)-3,4-dihydro-1H- (I-15) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H- (I-16) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H- (I-17) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H- (I-18) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H- (I-19) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H- (I-20) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H- (I-21) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2- (I-22) +++yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2- (I-23) +++yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H- (I-24) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H- (I-25) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H- (I-26) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- (I-27) +++pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- (I-28) +++pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H- (I-29) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-((2-chlorothiazol-5-yl)methyl)-N-hydroxy-2′-oxo-3,4- (I-30) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-((2-hydroxythiazol-5-yl)methyl)-2′-oxo-3,4- (I-31) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H- (I-32) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-33) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H- (I-34) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-35) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H- (I-36) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-37) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H- (I-38) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro- (I-39)+++ 1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-40) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4- (I-41) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo- (I-42)+++ 3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(R)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro- (I-43)+++ 1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H- (I-44) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2- (I-45) +++yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)- (I-46) +++2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(R)-N-hydroxy-1′-(2-methylallyl)-2′-oxo-3,4-dihydro-1H- (I-47) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2,5-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-48) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2,6-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-49) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-50) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro-1H- (I-51) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-ylmethyl)-3,4-dihydro-1H- (I-52) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-53) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-54) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-55) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H- (I-56) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-57) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro- (I-58) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4- (I-59) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H- (I-60) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-61) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H- (I-62) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-63) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro- (I-64) ++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-65) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H- (I-66) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4- (I-67) ++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-68) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4- (I-69) ++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo- (I-70)+++ 3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(S)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4- (I-71) ++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H- (I-72) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2- (I-73) +++yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2,5-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-74) ++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2,6-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-75) ++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-76) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro- (I-77) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-ylmethyl)-3,4-dihydro- (I-78) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-79) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(4-(trifluoromethoxy)benzyl)-3,4- (I-80) ++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-81) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-82) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro- (I-83) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-84) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(4-(tert-butyl)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-85) ++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro- (I-86) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4- (I-87) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(4-(methylsulfonyl)benzyl)-2′-oxo-3,4- (I-88) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(naphthalen-1-yl)-2′-oxo-3,4-dihydro-1H- (I-89) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-90) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(benzo[d][l,3]dioxol-5-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-91)+++ 1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(3-(methylthio)phenyl)-2′-oxo-3,4-dihydro- (I-92) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(4-(dimethylamino)phenyl)-N-hydroxy-2′-oxo-3,4- (I-93) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4- (I-94) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H- (I-95) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2,3-dihydrobenzofuran-7-yl)-N-hydroxy-2′-oxo-3,4- (I-96) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(6-(tert-butylamino)pyrimidin-4-yl)-N-hydroxy-2′-oxo-3,4- (I-97)+++ dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(1,3-dimethyl-1H-pyrazol-4-yl)-N-hydroxy-2′-oxo-3,4- (I-98) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4- (I-99) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2,4-dimethylphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-100) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4- (I-101) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(S)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H- (I-102) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4- (I-103) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H- (I-104) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H- (I-105) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)- (I-106)+++ 3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(S)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)- (I-107)++ 3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6- carboxamide(R)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro-1H- (I-108) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-109) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-110) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methoxyphenyl)-2′-oxo-3,4-dihydro- (I-111) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-112) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-113) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4- (I-114) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methoxyphenyl)-2′-oxo-3,4-dihydro- (I-115) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-116) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-117) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4- (I-118) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-119) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-120) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-121)spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro- (I-122) ++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-123) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(4-methoxyphenyl)-2′-oxo-3,4-dihydro-1H- (I-124) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-125) +++dihydro-lH-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-126) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-127) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-128) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-129) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(5-chloropyridin-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-130) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-131) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-132) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-133) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-134) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(5-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-135) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-136) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro- (I-137) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-138) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-139) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-140) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-141) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(4-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro- (I-142) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro- (I-143) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro- (I-144) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro- (I-145) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro- (I-146) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-147) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4- (I-148) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro- (I-149) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro- (I-150) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(6-(dimethylamino)pyridin-3-yl)-N-hydroxy-2′-oxo-3,4- (I-151) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(6-(dimethylamino)pyridin-3-yl)-N-hydroxy-2′-oxo-3,4- (I-152) ++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-153)+++ spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-154) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-155) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-156) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-157) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro- (I-158) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H- (I-159) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H- (I-160) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-161) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-162) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-163) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-164) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro- (I-165) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro- (I-166) ++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2,5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-167) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4- (I-168) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2,5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-169) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4- (I-170) +++dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-171) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-172) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(4-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-173) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(2-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-174) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(2-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-175) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-176) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamideN-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′- (I-177) +++piperidine]-6-carboxamide N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-(I-178) +++ spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H- (I-179) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H- (I-180) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H- (I-181) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H- (I-182) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-183) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-184) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-185) +++1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro- (I-186) +++1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-1′-(3-methoxypropyl)-2′-oxo-3,4-dihydro- (I-187) +++1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-N-hydroxy-1′-(3-methoxypropyl)-2′-oxo-3,4-dihydro- (I-188) +++1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H- (I-189) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H- (I-190) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H- (I-191) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H- (I-192) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-193) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-194) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro- (I-195) +++1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro- (I-196) +++1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-197) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-198) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-199) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(S)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H- (I-200) +++spiro[naphthalene-2,3′-piperidine]-6-carboxamide(R)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H- (I-201) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H- (I-202) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H- (I-203) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H- (I-204) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro- (I-205) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-ethyl-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-206) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-isobutyl-5′-oxo-3,4-dihydro-1H- (I-207) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-isopropyl-5′-oxo-3,4-dihydro-1H- (I-208) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-cyclopropyl-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-209) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro- (I-210) +++1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-ethyl-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-211) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-isobutyl-5′-oxo-3,4-dihydro-1H- (I-212) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-isopropyl-5′-oxo-3,4-dihydro-1H- (I-213) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-cyclopropyl-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-214) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(oxetan-3-ylmethyl)-5′-oxo-3,4-dihydro-1H- (I-215) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-benzyl-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-216) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-5′-oxo-3,4-dihydro-1H- (I-217) ++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-1′-benzyl-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-218) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(3-methoxypropyl)-5′-oxo-3,4-dihydro-1H- (I-219) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-5′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H- (I-220)+++ spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-5′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H- (I-221) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-1′-(3-methoxypropyl)-5′-oxo-3,4-dihydro-1H- (I-222) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-5′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H- (I-223)+++ spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(S)-N-hydroxy-5′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H- (I-224) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-1′-(2-methylbenzyl)-5′-oxo-3,4-dihydro-1H- (I-225) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H- (I-226) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-1′-(4-fluorophenyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H- (I-227) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H- (I-228) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(R)-N-hydroxy-5′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H- (I-229) +++spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamideN-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′- (I-230) +pyrrolidine]-6-carboxamideN-hydroxy-2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6- (I-231) ++carboxamide1′-benzyl-N-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6- (I-232) ++carboxamide N-hydroxy-2′-oxo-1′-(pyridin-3-yl)spiro[chromane-2,3′-(I-233) ++ pyrrolidine]-6-carboxamideN-hydroxy-2′-oxo-1′-((tetrahydro-2H-pyran-4- (I-234) +yl)methyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamideN-hydroxy-1′-isopropyl-2′-oxospiro[chromane-2,3′- (I-235) +pyrrolidine]-6-carboxamideN-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6- (I-236) ++carboxamideN-hydroxy-1′-methyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6- (I-237) ++carboxamideN-hydroxy-2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]- (I-238) ++6′-carboxamide 1′,1′-dioxide1-benzyl-N-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]- (I-239) ++6′-carboxamide 1′,1′-dioxideN-hydroxy-2-oxo-1-(pyridin-3-yl)spiro[pyrrolidine-3,2′- (I-240) ++thiochromane]-6′-carboxamide 1′,1′-dioxideN-hydroxy-2-oxo-1-((tetrahydro-2H-pyran-4- (I-241) +yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxideN-hydroxy-2-oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′- (I-242) +thiochromane]-6′-carboxamide 1′,1′-dioxideN-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′- (I-243) +carboxamide 1′,1′-dioxideN-hydroxy-1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]- (I-244) +6′-carboxamide 1′,1′-dioxideN-hydroxy-1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]- (II-1) +6-carboxamide 1′-((1H-benzo[d]imidazol-2-yl)methyl)-N- (II-2) +hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide1′-(cyclohexanecarbonyl)-N-hydroxyspiro[chromane-2,4′- (II-3) +piperidine]-6-carboxamideN-hydroxy-1′-(4-methoxybenzoyl)spiro[chromane-2,4′- (II-4) +piperidine]-6-carboxamideN-hydroxy-1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′- (II-5) +piperidine]-6-carboxamide1′-(cyclohexylsulfonyl)-N-hydroxyspiro[chromane-2,4′- (II-6) ++piperidine]-6-carboxamideN6-hydroxy-N1′-phenylspiro[chromane-2,4′-piperidine]-1′,6- (II-7) ++dicarboxamide 1′-cyclohexyl-N-hydroxyspiro[chromane-2,4′-piperidine]-6-(II-8) + carboxamideN-hydroxy-1′-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-(II-9) + carbonyl)spiro[chromane-2,4′-piperidine]-6-carboxamideEquivalents

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

The invention claimed is:
 1. A compound of the Formula I:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,tautomer, or isomer or thereof, wherein: X¹, X², X³, X⁶, and X⁷ are eachindependently —CR¹R²—, —NR³—, —O—, —C(O)—, —SO₂—, —S(O)—, or —S—; X⁴ andX⁵ are each independently —CR¹R²—, —C(O)—, —SO₂—, —S(O)—, or —S—; Y¹, Y³and Y⁴ are each independently N or CR¹; L is a bond, —(CR¹R²)_(n)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(n)O—,or —C(O)(CR¹R²)_(n)—; R is independently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₅-C₁₂spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, or O, whereineach alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R²,—SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, orheteroaryl; R¹ and R² are independently, at each occurrence, —H, —R³,—R⁴, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, or (CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more —OH, halogen,—NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴, —S(O)₂N(R³)₂—, —S(O)₂R⁵,—C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵,heterocycle, aryl, or heteroaryl; or R¹ and R² can combine with thecarbon atom to which they are both attached to form a cycloalkyl,heterocycle, spirocycle, spiroheterocycle, or spirocycloalkenyl; or R¹and R², when on adjacent or non-adjacent atoms, can combine to form aheterocycle, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatomsselected from the group consisting of N, S, P and O, or cycloalkenyl; R³and R⁴ are independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromN, S, P, and O, —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, or—(CHR⁵)_(n)N(C₁-C₆alkyl)₂, wherein each alkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with one or more substituents selected from —OH, halogen,—NO₂, oxo, —CN, —R⁵, —O(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N(C₁-C₆alkly)₂,—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂NHC₁-C₆alkyl, —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, —S(O)R⁵,—S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)R⁵, heterocycle, aryl, orheteroaryl; R⁵ is independently, at each occurrence, —H, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromN, S, P and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆alkyl,—S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl)or —(CH₂)_(n)N(C₁-C₆alkyl)₂; n is an integer from 0 to 6; and m is 0, 1,2 or
 3. 2. The compound of claim 1, wherein X⁴ is —C(O)—.
 3. Thecompound of claim 1, wherein m is 0 or
 1. 4. The compound of claim 1,wherein the compound is of the Formula I-a:


5. The compound of claim 1, wherein the compound is of the Formula I-b:


6. The compound of claim 1, wherein the compound is of the Formula I-c:


7. The compound of claim 1, wherein the compound is of the Formula I-d:


8. The compound of claim 1, wherein the compound is of the Formula I-e:


9. The compound of claim 1, wherein the compound is of the Formula I-f:


10. The compound of claim 1, wherein the compound is of the Formula I-g:


11. The compound of claim 1, wherein the compound is of the Formula I-h:


12. The compound of claim 1, wherein the compound is of the Formula I-j:


13. The compound of claim 1, wherein the compound is of the Formula I-k:


14. The compound of claim 1, wherein the compound is of the Formula I-m:


15. A compound of the Formula II:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,tautomer, or isomer or thereof, wherein: X¹ is independently —CR¹R²—,—NR³—, —O—, —SO₂—, —S(O)—, or —S—; X², X³, X⁴, and X⁷ are eachindependently —CR¹R²—, —NR³—, —O—, —C(O)—, —SO₂—, —S(O)—, or —S—; X⁵ andX⁶ are each independently —CR¹R²—, —C(O)—, —SO₂—, —S(O)—, or —S—; Y¹, Y³and Y⁴ are each independently N or CR¹; L is a bond, —(CR¹R²)_(n)—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, —S(O)NR³—, —C(O)(CR¹R²)_(n)O—,or —C(O)(CR¹R²)_(n)—; R is independently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₄-C₈cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈cycloalkyl, —C₅-C₁₂spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, or O, whereineach -alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R²,—SR³, —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, orheteroaryl; R¹ and R² are independently, and at each occurrence, —H,—R³, —R⁴, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, or O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆alkyl),—(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, or (CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more substituentsselected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴,—S(O)₂N(R³)₂—, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, or heteroaryl; or R¹ and R²can combine with the carbon atom to which they are both attached to forma cycloalkyl, heterocycle, spirocycle, spiroheterocycle, orspirocycloalkenyl; or R¹ and R², when on adjacent or non-adjacent atoms,can combine to form a heterocycle, cycloalkyl, aryl, heteroarylcontaining 1-5 heteroatoms selected from the group consisting of N, S, Pand O, or cycloalkenyl; R³ and R⁴ are independently, at each occurrence,—H, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆alkynyl,—C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from N, S, P and O, —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂(C₁-C₆alkyl), —(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl,—CO₂C₁-C₆alkyl, or —(CHR⁵)_(n)N(C₁-C₆alkyl)₂, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, andheteroaryl is optionally substituted with one or more substituentsselected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —O(C₁-C₆)alkyl,—NH(C₁-C₆)alkyl, —N(C₁-C₆alkly)₂, —S(O)₂N(C₁-C₆alkyl)₂,—S(O)₂NHC₁-C₆alkyl, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)S(O)₂C₁-C₆alkyl, —S(O)R⁵, —S(O)N(C₁-C₆alkyl)₂,—N(C₁-C₆alkyl)S(O)R⁵, heterocycle, aryl, or heteroaryl; each R⁵ isindependently —H, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₄-C₈cycloalkenyl,—C₂-C₆alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroarylcontaining 1-5 heteroatoms selected from N, S, O and P, —OH, halogen,—NO₂, —CN, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl),—S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆alkyl, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆alkyl,—N(C₁-C₆alkyl)SO₂C₁-C₆alkyl, —S(O)(C₁-C₆alkyl), —S(O)N(C₁-C₆alkyl)₂,—N(C₁-C₆alkyl)S(O)(C₁-C₆alkyl) or —(CH₂)_(n)N(C₁-C₆alkyl)₂; and n is aninteger from 0 to
 6. 16. The compound of claim 15, wherein X⁵ is C(O).17. The compound of claim 15 wherein the compound is of the FormulaII-a:


18. The compound of claim 15, wherein the compound is of the FormulaII-b:


19. The compound of claim 15, wherein the compound is of the FormulaII-c:


20. The compound of claim 15, wherein the compound is of the FormulaII-d:


21. The compound of claim 15, wherein the compound is of the FormulaII-e:


22. A compound of claim 1 selected from:1′-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-1);N-hydroxy-1′-(4-methoxyphenethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-2);N-hydroxy-1′-(4-methoxybenzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-3);N-hydroxy-1′-(4-methoxyphenethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-4);1′-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-5);1′-(3,4-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-6);1′-(cyclohexylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-7);N-hydroxy-1′-(4-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-8);1′-(3-(dimethylamino)propyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-9);(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-10);(S)-N-hydroxy-2′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-11);(R)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-12);(S)-N-hydroxy-1′-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-13);(R)-N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-14);(S)-N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-15);(R)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-16);(S)-N-hydroxy-2′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-17);(R)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-18);(S)-N-hydroxy-2′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-19);(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-20);(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-21);(R)-N-hydroxy-1′-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-22);(S)-N-hydroxy-1′-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-23);(R)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-24);(S)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-25);(R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-26);(R)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-27);(S)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-28);(S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-29);(R)-1′-((2-chlorothiazol-5-yl)methyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-30);(R)-N-hydroxy-1′-((2-hydroxythiazol-5-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-31);(R)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-32);(R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-33);(R)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-34);(R)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-35);(R)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-36);(R)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-37);(R)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-38);(R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-39);(R)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-40);(R)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-41);(R)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-42);(R)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-43);(R)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-44);(R)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-45);(R)-N-hydroxy-1′-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-46);(R)-N-hydroxy-1′-(2-methylallyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-47);(R)-1′-(2,5-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-48);(R)-1′-(2,6-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-49);(R)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-50);(R)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-51);(R)-N-hydroxy-2′-oxo-1′-(pyridin-2-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-52);(R)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-53);(R)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-54);(R)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-55);(R)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-56);(R)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-57);(R)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-58);(R)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-59);(S)-N-hydroxy-2′-oxo-1′-propyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-60);(S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-61);(S)-N-hydroxy-1′-isopentyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-62);(S)-1′-(but-2-yn-1-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-63);(S)-N-hydroxy-1′-(2-methoxyethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-64);(S)-1′-cinnamyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-65);(S)-N-hydroxy-1′-(2-methylbenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-66);(S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-67);(S)-1′-(2-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-68);(S)-N-hydroxy-2′-oxo-1′-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-69);(S)-1′-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-70);(S)-N-hydroxy-1′-(2-morpholino-2-oxoethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-71);(S)-N-hydroxy-1′-(2-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-72);(S)-N-hydroxy-1′-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-73);(S)-1′-(2,5-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-74);(S)-1′-(2,6-dichlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-75);(S)-1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-76);(S)-N-hydroxy-1′-(3-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-77);(S)-N-hydroxy-2′-oxo-1′-(pyridin-2-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-78);(S)-1′-(3-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-79);(S)-N-hydroxy-2′-oxo-1′-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-80);(S)-1′-(3-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-81);(S)-1′-(4-chlorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-82);(S)-N-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-83);(S)-1′-(2-fluorobenzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-84);(S)-1′-(4-(tert-butyl)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-85);(S)-N-hydroxy-1′-(naphthalen-2-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-86);(S)-1′-(2-(difluoromethoxy)benzyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-87);(R)-N-hydroxy-1′-(4-(methylsulfonyl)benzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-88);(R)-N-hydroxy-1′-(naphthalen-1-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-89);(R)-1′-(3-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-90);(R)-1′-(benzo[d][1,3]dioxol-5-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-91);(R)-N-hydroxy-1′-(3-(methylthio)phenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-92);(R)-1′-(4-(dimethylamino)phenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-93);(R)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-94);(R)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-95);(R)-1′-(2,3-dihydrobenzofuran-7-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-96);(R)-1′-(6-(tert-butylamino)pyrimidin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-97);(R)-1′-(1,3-dimethyl-1H-pyrazol-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-98);(R)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-99);(S)-1′-(2,4-dimethylphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-100);(S)-N-hydroxy-1′-(6-isopropylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-101);(S)-N-hydroxy-2′-oxo-1′-(quinolin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-102);(S)-N-hydroxy-1′-(imidazo[1,2-a]pyridin-6-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-103);(R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-104);(S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-105);(R)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-106);(S)-N-hydroxy-2′-oxo-1′-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-107);(R)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-108);(R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-109);(R)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-110);(R)-N-hydroxy-1′-(2-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-111);(R)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-112);(R)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-113);(R)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-114);(S)-N-hydroxy-1′-(2-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-115);(S)-1′-(3-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-116);(S)-1′-(3-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-117);(S)-N-hydroxy-1′-(6-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-118);(R)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-119);(R)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-120);(R)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-121);(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-122);(R)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-123);(R)-N-hydroxy-1′-(4-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-124);(R)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-125);(S)-1′-(2-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-126);(S)-1′-(2-fluoro-4-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-127);(R)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-128);(S)-1′-(4-fluoro-3-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-129);(S)-1′-(5-chloropyridin-2-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-130);(R)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-131);(S)-N-hydroxy-1′-(2-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-132);(R)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-133);(S)-N-hydroxy-1′-(6-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-134);(R)-N-hydroxy-1′-(5-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-135);(R)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-136);(S)-N-hydroxy-1′-(4-methylpyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-137);(R)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-138);(S)-1′-(5-chloropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-139);(R)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-140);(S)-1′-(3-chloropyridin-4-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-141);(S)-N-hydroxy-1′-(4-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-142);(R)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-143);(S)-N-hydroxy-1′-(5-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-144);(R)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-145);(S)-N-hydroxy-1′-(2-methoxypyridin-3-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-146);(S)-1′-(2-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-147);(S)-1′-(3-fluoro-5-methoxyphenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-148);(R)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-149);(S)-N-hydroxy-1′-(2-methoxypyridin-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-150);(R)-1′-(6-(dimethylamino)pyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-151);(S)-1′-(6-(dimethylamino)pyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-152);(S)-1′-(5-fluoropyridin-3-yl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-153);(S)-1′-(4-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-154);(S)-1′-(3,4-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-155);(S)-1′-(2,3-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-156);(S)-1′-(2-fluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-157);(S)-N-hydroxy-1′-(3-methoxyphenyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-158);(R)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-159);(S)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-160);(R)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-161);(S)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-162);(R)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-163);(S)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-164);(R)-N-hydroxy-2′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-165);(S)-N-hydroxy-2′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-166); (R)-1′-(2,5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-167);(R)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-168);(S)-1′-(2,5-difluorophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-169);(S)-N-hydroxy-1′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-170);(R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-171);(S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-172);(S)-1′-(4-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-173);(S)-1′-(2-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-174);(R)-1′-(2-cyanophenyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-175);1′-benzyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-176);N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-177);N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-178);(R)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-179);(S)-N-hydroxy-1′-methyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-180);(R)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-181);(S)-N-hydroxy-2′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-182);(S)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-183);(S)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-184);(R)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-185);(S)-1′-(cyclobutylmethyl)-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-186);(R)-N-hydroxy-1′-(3-methoxypropyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-187);(S)-N-hydroxy-1′-(3-methoxypropyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-188);(R)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-189);(S)-N-hydroxy-1′-isobutyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-190);(R)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-191);(S)-N-hydroxy-1′-isopropyl-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-192);(R)-1′-cyclopropyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-193);(R)-1′-ethyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-194);(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-195);(R)-N-hydroxy-1′-(oxetan-3-ylmethyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-196);(R)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-197);(S)-1′-cyclobutyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-198);(R)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-199);(S)-1′-cyclopentyl-N-hydroxy-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-200);(R)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-201);(S)-N-hydroxy-1′-methyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-202);(R)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-203);(S)-N-hydroxy-5′-oxo-1′-phenyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-204);(R)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-205);(R)-1′-ethyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-206);(R)-N-hydroxy-1′-isobutyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-207);(R)-N-hydroxy-1′-isopropyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-208);(R)-1′-cyclopropyl-N-hydroxy-5′-oxo-3,4-dihydro-H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-209);(S)-1′-(cyclobutylmethyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-210);(S)-1′-ethyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-211);(S)-N-hydroxy-1′-isobutyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-212);(S)-N-hydroxy-1′-isopropyl-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-213);(S)-1′-cyclopropyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-214);(R)-N-hydroxy-1′-(oxetan-3-ylmethyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-215);(R)-1′-benzyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-216);(S)-N-hydroxy-1′-(oxetan-3-ylmethyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-217);(S)-1′-benzyl-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-218);(R)-N-hydroxy-1′-(3-methoxypropyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-219);(R)-N-hydroxy-5′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-220);(R)-N-hydroxy-5′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-221);(S)-N-hydroxy-1′-(3-methoxypropyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-222);(S)-N-hydroxy-5′-oxo-1′-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-223);(S)-N-hydroxy-5′-oxo-1′-(pyridin-3-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-224);(R)-N-hydroxy-1′-(2-methylbenzyl)-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-225);(R)-N-hydroxy-5′-oxo-1′-(pyridin-3-ylmethyl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-226);(R)-1′-(4-fluorophenyl)-N-hydroxy-5′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-227);(R)-N-hydroxy-5′-oxo-1′-(pyridin-4-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-228);(R)-N-hydroxy-5′-oxo-1′-(pyridin-2-yl)-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxamide(I-229);N-hydroxy-2′-oxo-1′-(pyridin-4-ylmethyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-230);N-hydroxy-2′-oxo-1′-phenylspiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-231);1′-benzyl-N-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-232);N-hydroxy-2′-oxo-1′-(pyridin-3-yl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-233);N-hydroxy-2′-oxo-1′-((tetrahydro-2H-pyran-4-yl)methyl)spiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-234);N-hydroxy-1′-isopropyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-235); N-hydroxy-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-236);N-hydroxy-1′-methyl-2′-oxospiro[chromane-2,3′-pyrrolidine]-6-carboxamide(I-237);N-hydroxy-2-oxo-1-phenylspiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-238);1-benzyl-N-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-239);N-hydroxy-2-oxo-1-(pyridin-3-yl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-240);N-hydroxy-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-241);N-hydroxy-2-oxo-1-(pyridin-4-ylmethyl)spiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-242);N-hydroxy-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-243); orN-hydroxy-1-methyl-2-oxospiro[pyrrolidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-244).
 23. A compound of claim 15 selected from:N-hydroxy-1′-(4-methoxybenzyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-1);1′-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-2);1′-(cyclohexanecarbonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-3);N-hydroxy-1′-(4-methoxybenzoyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-4);N-hydroxy-1′-((4-methoxyphenyl)sulfonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-5);1′-(cyclohexylsulfonyl)-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-6);N6-hydroxy-N1′-phenylspiro[chromane-2,4′-piperidine]-1′,6-dicarboxamide(II-7);1′-cyclohexyl-N-hydroxyspiro[chromane-2,4′-piperidine]-6-carboxamide(II-8); orN-hydroxy-1′-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)spiro[chromane-2,4′-piperidine]-6-carboxamide(II-9).
 24. A compound of claim 1 selected from:N-hydroxy-1′-methyl-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-245);N-hydroxy-1-methyl-3′,4′-dihydro-1′H-spiro[azepane-3,2′-naphthalene]-6′-carboxamide(I-246);N-hydroxy-1-methyl-3′,4′-dihydro-1′H-spiro[azocane-3,2′-naphthalene]-6′-carboxamide(I-247);N-hydroxy-1-methyl-2-oxo-3′,4′-dihydro-1′H-spiro[azepane-3,2′-naphthalene]-6′-carboxamide(I-248);N-hydroxy-1-methyl-2-oxo-3′,4′-dihydro-1′H-spiro[azocane-3,2′-naphthalene]-6′-carboxamide(I-249);N-hydroxy-1′-methyl-6′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-piperidine]-6-carboxamide(I-250);N-hydroxy-1-methyl-7-oxo-3′,4′-dihydro-1′H-spiro[azepane-3,2′-naphthalene]-6′-carboxamide(I-251);N-hydroxy-1-methyl-8-oxo-3′,4′-dihydro-1′H-spiro[azocane-3,2′-naphthalene]-6′-carboxamide(I-252);N-hydroxy-1′-methyl-2′-oxospiro[chromane-2,3′-piperidine]-6-carboxamide(I-253);N-hydroxy-1-methyl-2-oxospiro[azepane-3,2′-chromane]-6′-carboxamide(I-254);N-hydroxy-1-methyl-2-oxospiro[azocane-3,2′-chromane]-6′-carboxamide(I-255);N-hydroxy-1-methyl-2-oxospiro[piperidine-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-256);N-hydroxy-1-methyl-2-oxospiro[azepane-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-257); orN-hydroxy-1-methyl-2-oxospiro[azocane-3,2′-thiochromane]-6′-carboxamide1′,1′-dioxide (I-258).
 25. A pharmaceutical composition comprising acompound of claim 1 or claim 15 and a pharmaceutically acceptablecarrier.
 26. A method of treating a cancer selected from melanoma,cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma,leukemia, lung cancer, ovarian cancer, breast cancer, prostate cancer,pancreatic cancer, hepatocellular cancer, renal cancer, squamous cellcarcinoma, lymphoma, non-small cell lung cancer, myeloproliferativeneoplasm, metastatic solid tumor, myelodysplastic syndrome, urothelialcancer, or myelofibrosis in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound of claim1 or claim
 15. 27. A method of treating a neurodegenerative diseaseselected from Alzheimer's, Huntington's, Parkinson's, AmyotrophicLateral Sclerosis, Charcot-Marie-Tooth Disease, depression, RettSyndrome, or spinal muscular atrophy in a subject in need thereof,comprising administering to the subject an effective amount of acompound of claim 1 or claim
 15. 28. A method of treating animmunological disease selected from rheumatoid arthritis, spondylitisarthritis, psoriatic arthritis, psoriasis, multiple sclerosis, systemiclupus erythematosus, inflammatory bowel diseases, graft versus hostdisease, transplant rejection or fibrotic disease in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of claim 1 or claim
 15. 29. A method of inhibiting a histonedeacetylase, comprising administering to a subject in need thereof acompound of claim 1 or claim
 15. 30. The method of claim 29, wherein thecompound inhibits a zinc-dependent histone deacetylase.
 31. The methodof claim 30, wherein the compound inhibits the HDAC6 isozymezinc-dependent histone deacetylase.
 32. The method of claim 26, whereinthe lymphoma is selected from B-cell lymphoma or non-Hodgkin's lymphoma.33. The method of claim 26, wherein the leukemia is selected from acutemyeloid leukemia and chronic lymphocytotic leukemia.